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  • 1.
    Abraham, Mark James
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Apostolov, Rossen
    KTH, School of Electrical Engineering and Computer Science (EECS), Centres, Centre for High Performance Computing, PDC.
    Barnoud, Jonathan
    Univ Groningen, NL-9712 CP Groningen, Netherlands.;Univ Bristol, Intangible Real Lab, Bristol, Avon, England..
    Bauer, Paul
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blau, Christian
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bonvin, Alexandre M. J. J.
    Univ Utrecht, Bijvoet Ctr, Fac Sci, Utrecht, Netherlands..
    Chavent, Matthieu
    Univ Paul Sabatier, IPBS, F-31062 Toulouse, France..
    Chodera, John
    Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA..
    Condic-Jurkic, Karmen
    Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA.;Open Force Field Consortium, La Jolla, CA USA..
    Delemotte, Lucie
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Grubmueller, Helmut
    Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany..
    Howard, Rebecca
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jordan, E. Joseph
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, SE-17121 Solna, Sweden..
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ollila, O. H. Samuli
    Univ Helsinki, Inst Biotechnol, SF-00100 Helsinki, Finland..
    Selent, Jana
    Pompeu Fabra Univ, Hosp del Mar Med Res Inst IMIM, Res Programme Biomed Informat, Barcelona 08002, Spain.;Pompeu Fabra Univ, Dept Expt & Hlth Sci, Barcelona 08002, Spain..
    Smith, Daniel G. A.
    Mol Sci Software Inst, Blacksburg, VA 24060 USA..
    Stansfeld, Phillip J.
    Univ Oxford, Dept Biochem, Oxford OX1 2JD, England.;Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England.;Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England..
    Tiemann, Johanna K. S.
    Univ Leipzig, Fac Med, Inst Med Phys & Biophys, D-04107 Leipzig, Germany..
    Trellet, Mikael
    Univ Utrecht, Bijvoet Ctr, Fac Sci, Utrecht, Netherlands..
    Woods, Christopher
    Univ Bristol, Bristol BS8 1TH, Avon, England..
    Zhmurov, Artem
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sharing Data from Molecular Simulations2019In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, no 10, p. 4093-4099Article in journal (Refereed)
    Abstract [en]

    Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 (https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.

  • 2.
    Abraham, Mark James
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Physics, Theoretical Biological Physics.
    Murtola, Teemu
    Schulz, Roland
    Pall, Szilard
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Physics, Theoretical Biological Physics.
    Smith, Jeremy C.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Physics, Theoretical Biological Physics.
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Physics, Theoretical Biological Physics.
    GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers2015In: SoftwareX, E-ISSN 2352-7110, Vol. 1-2, p. 19-25Article in journal (Refereed)
    Abstract [en]

    GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules. It provides a rich set of calculation types, preparation and analysis tools. Several advanced techniques for free-energy calculations are supported. In version 5, it reaches new performance heights, through several new and enhanced parallelization algorithms. These work on every level; SIMD registers inside cores, multithreading, heterogeneous CPU–GPU acceleration, state-of-the-art 3D domain decomposition, and ensemble-level parallelization through built-in replica exchange and the separate Copernicus framework. The latest best-in-class compressed trajectory storage format is supported.

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  • 3.
    Alekseenko, Andrej
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Pall, Szilard
    KTH, School of Electrical Engineering and Computer Science (EECS), Centres, Centre for High Performance Computing, PDC.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Experiences with Adding SYCL Support to GROMACS2021In: IWOCL'21: Proceedings International Workshop on OpenCL IWOCL 2021, Association for Computing Machinery (ACM) , 2021Conference paper (Refereed)
    Abstract [en]

    GROMACS is an open-source, high-performance molecular dynamics (MD) package primarily used for biomolecular simulations, accounting for 5% of HPC utilization worldwide. Due to the extreme computing needs of MD, significant efforts are invested in improving the performance and scalability of simulations. Target hardware ranges from supercomputers to laptops of individual researchers and volunteers of distributed computing projects such as Folding@Home. The code has been designed both for portability and performance by explicitly adapting algorithms to SIMD and data-parallel processors. A SIMD intrinsic abstraction layer provides high CPU performance. Explicit GPU acceleration has long used CUDA to target NVIDIA devices and OpenCL for AMD/Intel devices. In this talk, we discuss the experiences and challenges of adding support for the SYCL platform into the established GROMACS codebase and share experiences and considerations in porting and optimization. While OpenCL offers the benefits of using the same code to target different hardware, it suffers from several drawbacks that add significant development friction. Its separate-source model leads to code duplication and makes changes complicated. The need to use C99 for kernels, while the rest of the codebase uses C++17, exacerbates these issues. Another problem is that OpenCL, while supported by most GPU vendors, is never the main framework and thus is not getting the primary support or tuning efforts. SYCL alleviates many of these issues, employing a single-source model based on the modern C++ standard. In addition to being the primary platform for Intel GPUs, the possibility to target AMD and NVIDIA GPUs through other implementations (e.g., hipSYCL) might make it possible to reduce the number of separate GPU ports that have to be maintained. Some design differences from OpenCL, such as flow directed acyclic graphs (DAGs) instead of in-order queues, made it necessary to reconsider the GROMACS's task scheduling approach and architectural choices in the GPU backend. Additionally, supporting multiple GPU platforms presents a challenge of balancing performance (low-level and hardware-specific code) and maintainability (more generalization and code-reuse). We will discuss the limitations of the existing codebase and interoperability layers with regards to adding the new platform; the compute performance and latency comparisons; code quality considerations; and the issues we encountered with SYCL implementations tested. Finally, we will discuss our goals for the next release cycle for the SYCL backend and the overall architecture of GPU acceleration code in GROMACS.

  • 4.
    Andersson, Magnus
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Lindahl, Erik
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    White, Stephen H.
    Univ Calif Irvine, Irvine, CA USA..
    Kaback, Ronald H.
    Univ Calif Los Angeles, Los Angeles, CA USA..
    The Molecular Basis for Substrate Specificity in Lactose Permease2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 309A-309AArticle in journal (Other academic)
  • 5.
    Andersson, Magnus
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mattle, Daniel
    Sitsel, Oleg
    Nielsen, Anna Marie
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    White, Stephen H.
    Nissen, Poul
    Gourdon, Pontus
    Transport Pathway in Cu+ P-Type ATPases2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 427A-427AArticle in journal (Other academic)
  • 6.
    Apostolov, Rossen
    et al.
    KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Axner, Lilit
    KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Agren, Hans
    Ayugade, Eduard
    Duta, Mihai
    Gelpi, Jose Luis
    Gimenez, Judit
    Goni, Ramon
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Jamitzky, Ferdinand
    Kranzmuller, Dieter
    Labarta, Jesus
    Laure, Erwin
    KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Orozco, Modesto
    Peterson, Magnus
    Satzger, Helmut
    Trefethen, Anne
    Scalable Software Services for Life Science2011In: Proceedings of 9th HealthGrid conference, 2011Conference paper (Refereed)
    Abstract [en]

    Life Science is developing into one of the largest e- Infrastructure users in Europe, in part due to the ever-growing amount of biological data. Modern drug design typically includes both sequence bioinformatics, in silico virtual screening, and free energy calculations, e.g. of drug binding. This development will accelerate tremendously, and puts high demands on simulation software and support services. e-Infrastructure projects such as PRACE/DEISA have made important advances on hardware and scalability, but have largely been focused on theoretical scalability for large systems, while typical life science applications rather concern small-to-medium size molecules. Here, we propose to address this with by implementing new techniques for efficient small-system parallelization combined with throughput and ensemble computing to enable the life science community to exploit the largest next-generation e-Infrastructures. We will also build a new cross-disciplinary Competence Network for all of life science, to position Europe as the world-leading community for development and maintenance of this software e-Infrastructure. Specifically, we will (1) develop new hierarchical parallelization approaches explicitly based on ensemble and high-throughput computing for new multi-core and streaming/GPU architectures, and establish open software standards for data storage and exchange, (2) implement, document, and maintain such techniques in pilot European open-source codes such as the widely used GROMACS & DALTON, a new application for ensemble simulation (DISCRETE), and large-scale bioinformatics protein annotation, (3) create a Competence Centre for scalable life science software to strengthen Europe as a major software provider and to enable the community to exploit e-Infrastructures to their full extent. This Competence Network will provide training and support infrastructure, and establish a long-term framework for maintenance and optimization of life science codes.

  • 7.
    Axelsson, Linnea S.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Solna, Sweden..
    Rovsnik, Urska
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Solna, Sweden..
    Blau, Christian
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lycksell, Marie
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Solna, Sweden..
    Lim, Victoria
    Univ Calif Irvine, Irvine, CA USA..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Solna, Sweden..
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Balancing Stereochemistry and Goodness-of-Fit for Automated Simulation-Based Refinement into Cryo-EM Maps2021In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 120, no 3, p. 173A-173AArticle in journal (Other academic)
  • 8.
    Azuara, Cyril
    et al.
    Institut Pasteur, Paris France.
    Lindahl, Erik
    Stockholm University.
    Koehl, Patrice
    University of California, Davis.
    Orland, Henri
    Institut Pasteur, Paris, France.
    Delarue, Marc
    Institut Pasteur, Paris, France.
    PDB_Hydro: incorporating dipolar solvents with variable density in the Poisson-Boltzmann treatment of macromolecule electrostatics.2006In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 34, no Web Server issue, p. W38-42Article in journal (Refereed)
    Abstract [en]

    We describe a new way to calculate the electrostatic properties of macromolecules which eliminates the assumption of a constant dielectric value in the solvent region, resulting in a Generalized Poisson-Boltzmann-Langevin equation (GPBLE). We have implemented a web server (http://lorentz.immstr.pasteur.fr/pdb_hydro.php) that both numerically solves this equation and uses the resulting water density profiles to place water molecules at preferred sites of hydration. Surface atoms with high or low hydration preference can be easily displayed using a simple PyMol script, allowing for the tentative prediction of the dimerization interface in homodimeric proteins, or lipid binding regions in membrane proteins. The web site includes options that permit mutations in the sequence as well as reconstruction of missing side chain and/or main chain atoms. These tools are accessible independently from the electrostatics calculation, and can be used for other modeling purposes. We expect this web server to be useful to structural biologists, as the knowledge of solvent density should prove useful to get better fits at low resolution for X-ray diffraction data and to computational biologists, for whom these profiles could improve the calculation of interaction energies in water between ligands and receptors in docking simulations.

  • 9.
    Bergh, Cathrine
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Heusser, Stephanie A.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.;Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark..
    Howard, Rebecca
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel2021In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e68369Article in journal (Refereed)
    Abstract [en]

    Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.

  • 10.
    Bergh, Cathrine
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Orellana, Laura
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics. Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Understanding the Conformational Dynamics of a Pentameric Ligand-Gated Ion Channel through Markov State Modeling2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 395A-396AArticle in journal (Other academic)
  • 11.
    Bergh, Cathrine
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Rovsnik, Urska
    Howard, Rebecca J
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
    Discovery of lipid binding sites in a ligand-gated ion channel by integrating simulations and cryo-EM2024In: eLife, ISSN 2050-084X, Vol. 12, p. 2023-01Article in journal (Refereed)
    Abstract [en]

    Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside fromcanonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ionchannels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution ofthese regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLICby integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipidsin the GLIC closed state, a conformation where none, to our knowledge, were previously known. Three lipidswere associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutantsimulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, whilea putative intersubunit site was preferred in open-state simulations. This work offers molecular details ofGLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependentbinding, and a multidisciplinary strategy for modeling protein-lipid interactions.

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  • 12.
    Bergh, Cathrine
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Rovsnik, Urska
    Sci Life Lab, Solna, Sweden.;Stockholm Univ, Stockholm, Sweden..
    Howard, Rebecca
    Sci Life Lab, Solna, Sweden.;Stockholm Univ, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Integrating simulations and cryo-EM reveal lipid binding sites in a ligand-gated ion channel2023In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 52, no SUPPL 1, p. S118-S118Article in journal (Other academic)
  • 13.
    Bernsel, Andreas
    et al.
    Stockholm University.
    Viklund, Håkan
    Stockholm University.
    Falk, Jenny
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    von Heijne, Gunnar
    Stockholm University.
    Elofsson, Arne
    Stockholm University.
    Prediction of membrane-protein topology from first principles2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 20, p. 7177-7781Article in journal (Refereed)
    Abstract [en]

    The current best membrane-protein topology-prediction methods are typically based on sequence statistics and contain hundreds of parameters that are optimized on known topologies of membrane proteins. However, because the insertion of transmembrane helices into the membrane is the outcome of molecular interactions among protein, lipids and water, it should be possible to predict topology by methods based directly on physical data, as proposed >20 years ago by Kyte and Doolittle. Here, we present two simple topology-prediction methods using a recently published experimental scale of position-specific amino acid contributions to the free energy of membrane insertion that perform on a par with the current best statistics-based topology predictors. This result suggests that prediction of membrane-protein topology and structure directly from first principles is an attainable goal, given the recently improved understanding of peptide recognition by the translocon.

  • 14. Bertaccini, E. J.
    et al.
    Yoluk, Özge
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik R.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Trudell, James Robert
    Department of Anesthesia, Stanford University School of Medicine, United States .
    Assessment of homology templates and an anesthetic binding site within the ?-aminobutyric acid receptor2013In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 119, no 5, p. 1087-1095Article in journal (Refereed)
    Abstract [en]

    Background: Anesthetics mediate portions of their activity via modulation of the ?-aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling. Methods: The structure of the torpedo acetylcholine receptor (nAChR?), the structures of the ?4 and ?2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50s. Results: Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between ? and ? subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50. Conclusion: Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.

  • 15.
    Bertaccini, Edward J.
    et al.
    Stanford University.
    Lindahl, Erik
    Stockholm University.
    Sixma, Titia
    Netherlands Cancer Institute.
    Trudell, James R.
    Stanford University.
    Effect of cobratoxin binding on the normal mode vibration within acetylcholine binding protein2008In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 48, no 4, p. 855-860Article in journal (Refereed)
    Abstract [en]

    Recent crystal structures of the acetylcholine binding protein (AChBP) have revealed surprisingly small structural alterations upon ligand binding. Here we investigate the extent to which ligand binding may affect receptor dynamics. AChBP is a homologue of the extracellular component of ligand-gated ion channels (LGICs). We have previously used an elastic network normal-mode analysis to propose a gating mechanism for the LGICs and to suggest the effects of various ligands on such motions. However, the difficulties with elastic network methods lie in their inability to account for the modest effects of a small ligand or mutation on ion channel motion. Here, we report the successful application of an elastic network normal mode technique to measure the effects of large ligand binding on receptor dynamics. The present calculations demonstrate a clear alteration in the native symmetric motions of a protein due to the presence of large protein cobratoxin ligands. In particular, normal-mode analysis revealed that cobratoxin binding to this protein significantly dampened the axially symmetric motion of the AChBP that may be associated with channel gating in the full nAChR. The results suggest that alterations in receptor dynamics could be a general feature of ligand binding.

  • 16.
    Bertaccini, Edward J
    et al.
    Stanford University.
    Lindahl, Erik
    Stanford University.
    Titia, Sixma
    Netherlands Cancer Institute.
    Trudell, James R
    Stanford University.
    Toxin Binding Serves as an Initial Model for Studying the Effects of Anesthetics on Ion Channels2007Conference paper (Refereed)
    Abstract [en]

    Introduction: We have previously used molecular modeling techniques combined with experimental data to visualize a plausible model of an anesthetic binding site within a LGIC complex.We have also previously shown a computational mechanism by which these ion channels may open and close and postulated how this motion may be affected by the presence of anesthetics.2 The difficulties with these methods, however, lay in their inability to account for the modest effects of a separate anesthetic ligand or small mutation on ion channel motion. Here we show the successful application of an elastic network calculation on a homologue of the extracellular component of LGIC's, the acetycholine binding protein (AChBP), in the presence and absence of large cobratoxin ligands. These calculations demonstrate a clear alteration in the native symmetric motion of a protein due to the presence of multiple ligands, as may occur with anesthetics and muscle relaxants.

    Methods: Coordinates of the AChBP with (1YI5)3 and without (1I9B)4 cobratoxin were obtained from the Research Collaboratory for Structural Biology (RCSB). Hydrogens were added using DSViewer 5.0 (Accelrys, San Diego, CA). Normal mode analysis was performed using an all atom elastic network model developed by Lindahl. Root-mean-square deviations (RMSD) of each residue were produced from the application of the RMSD analysis utility within the GROMACS software suite to the coordinate trajectory output files. The RMSD data was then imported into Microsoft Excel for plotting and further comparison of protein backbone motions between the two different normal mode trajectories.

    Results: Normal mode analysis reveals that ligand binding to this protein alters its natural harmonic vibration. In this case, the axially symmetric motion of the AChBP, that may be associated with channel gating in the full nAChR, is highly dampened by the presence of bound cobratoxin. A large proportion of the kinetic energy within this mode seems to be absorbed by the cobratoxin, leaving the channel motion significantly decreased.

    Conclusions: This is among the first descriptions of the effect of bound ligand on large scale protein dynamics, especially as it relates to ion channel gating. This analysis was possible using an elastic network approximation due to the large protein nature of the cobratoxin ligand. For nonpeptide drugs such as anesthetics which contain far fewer atoms, using the effects of bound ligand on protein motion as additional criteria for future drug design may require a more robust molecular mechanics treatment of the ligand-receptor complex.

  • 17.
    Bertaccini, Edward J.
    et al.
    Stanford University.
    Trudell, James R.
    Stanford University.
    Lindahl, Erik
    Stockholm University.
    Normal-mode analysis of the glycine alpha1 receptor by three separate methods2007In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 47, no 4, p. 1572-1579Article in journal (Refereed)
    Abstract [en]

    Predicting collective dynamics and structural changes in biological macromolecules is pivotal toward a better understanding of many biological processes. Limitations due to large system sizes and inaccessible time scales have prompted the development of alternative techniques for the calculation of such motions. In this work, we present the results of a normal-mode analysis technique based on molecular mechanics that enables the calculation of accurate force-field based vibrations of extremely large molecules and compare it with two elastic network approximate models. When applied to the glycine alpha1 receptor, all three normal-mode analysis algorithms demonstrate an "iris-like" gating motion. Such gating motions have implications for understanding the effects of anesthetic and other ligand binding sites and for the means of transducing agonist binding into ion channel opening. Unlike the more approximate methods, molecular mechanics based analyses can also reveal approximate vibrational frequencies. Such analyses may someday allow the use of protein dynamics elucidated via normal-mode calculations as additional endpoints for future drug design.

  • 18.
    Bertaccini, Edward J
    et al.
    Stanford University.
    Trudell, James R
    Stanford University.
    Lindahl, Erik
    Stockholm University.
    Understanding Effects of Anesthetics on Ligand-Gated Ion Channels (LGIC) in Lipid Membranes2008Conference paper (Refereed)
    Abstract [en]

    Introduction: We have previously used molecular modeling combined with experimental data to visualize a plausible model of an anesthetic binding site within a LGIC.1 We have also previously shown a computational mechanism by which these LGICs may gate and postulated how this motion may be affected by the presence of anesthetics.2 The initial difficulty with these calculations concerns the 26000 atoms present in the receptor and the computing capabilities required to perform vibrational analyses on such a large construct. Here we show the successful application of an elastic network calculation on our previously published model of a glycine alpha one receptor (GlyRa1), now suspended in a fully hydrated lipid bilayer. Despite the presence of over 100,000 atoms , these calculations continue to demonstrate a symmetric motion of the ion channel protein that is consistent with the gating motion demonstrated in previous in vacuo work by us and others. Methods: Coordinates of the GlyRa1 model were obtained from our previous work. A 100x100A lipid bilayer matrix was constructed from POPC and then hydrated on both surfaces with water molecules using the VMD 1.86 software package (NCSA, Urbana, Ill.). Discovery Studio 1.7 (Accelrys, San Diego, CA) molecular modeling software was used to insert our GlyRa1 model into the lipid bilayer such that the known interfacial residue GLY 221 was at the POPC-water interface. All waters within 3.8A of the protein were removed as were all lipid molecules within 2A of the protein. Hydrogens were added followed by energy minimization of the entire system to remove energetically unfavorable contacts. The system was subsequently further hydrated within the GROMACS software suite and subjected to further energy equilibration via molecular dynamics simulation with periodic boundary conditions. Subsequent normal mode analysis was performed using an all atom elastic network model developed by Lindahl which takes advantage of a sparse matrix implementation for computational efficiency. Results: Despite the large size of the system, the introduction of water and lipid did not grossly distort the overall gating motion of the glyRa1 noted in previous works. Normal mode analysis revealed that the GlyRa1 in a fully hydrated bilayer environment continues to demonstrate an iris-like gating motion as a low frequency, high amplitude natural harmonic vibration. Furthermore, the introduction of periodic boundary conditions allowed simultaneous harmonic vibrations of lipid in sync with the protein gating motion that are compatible with reasonable lipid bilayer perturbations. Conclusions: This is among the first description of a normal mode calculation describing large-scale protein dynamics and ion channel gating in the presence of a fully hydrated lipid bilayer complex. This analysis was only possible on such a large system due to the computational efficiencies of the elastic network approximation. This model will hopefully provide a more accurate means of introducing anesthetics and alcohols into protein and lipid bilayer systems and allow us to discern their effects on LGIC gating. 1Bertaccini EJ, Shapiro J, Brutlag DL, Trudell JR: J Chem Inf Model 2005; 45: 128-35; 2Bertaccini EJ, Trudell JR, Lindahl E:J Chem Inf Model 2007; 47: 1572-9.

  • 19.
    Bertaccini, Edward J.
    et al.
    Stanford University.
    Trudell, James R.
    Stanford University.
    Lindahl, Erik
    Stockholm University.
    Murail, Samuel
    Stockholm University.
    Anesthetic Binding Sites in a GlyRa1 Model Based on Open State Prokaryotic Ion Channel Templates2009In: Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists, 2009Conference paper (Refereed)
    Abstract [en]

    Introduction : Ligand-gated ion channels (LGICs) are thought to mediate a significant proportion of anesthetic effects. We built atomic level models of the glycine alpha one receptor (GlyRa1) to examine its interactions with anesthetics. We previously built models of a GlyRa1 based on a prokaryotic pentameric ion channel in the closed state from Erwinia Chrysanthemi (ELIC) (1-3). Here, we built a GlyRa1 model based on the open state structures of two new ion channels from the prokaryote Gloebacter violaceus (GLIC).(4-5) These new templates are relevant since anesthetics are thought to bind to and stabilize the open state of the GlyRa1. Methods : The 3D coordinates of two forms of GLIC (3EHZ.pdb and 3EAM.pdb) were obtained from the RCSB database. The sequence of the human GlyRa1 was obtained from the NCBI database. A BLAST sequence search was performed using the GLIC sequences. Among the best scored homologous human sequences were those of the GlyRa1. The template structures and the sequence of GlyRa1 were aligned with Discovery Studio 2.0.1 (Accelrys, San Diego, CA) and the Modeler module was used for assignment of coordinates for aligned amino acids, the construction of possible loops, and the initial refinement of amino acid sidechains. Results : The BLAST derived scores suggest a close homology between the LGICs, GLIC and ELIC. Subsequent CLUSTALW alignment of the GLIC and GlyRa1 sequences demonstrates reasonable sequence similarity. The model of the GlyRa1 is a homomer with pentameric symmetry about a central ion pore and shows significant transmembrane alpha helical and extracellular beta sheet content. Unlike our previous model based on the ELIC template, the current model based on the GLIC templates shows a continuously open pore with a partial restriction within the transmembrane region. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3) (ILE229, SER 267, ALA 288). They now line the intersubunit interface, in contrast to our previous models. However, residues from TM4 that are known to modulate a variety of anesthetic effects on this or homologous LGICs are present but could only indirectly influence an intersubunit anesthetic binding site. Normal mode analyses show an iris-like motion similar to previous results.Conclusions : A model of the GlyRa1 was constructed using homology modeling based on the GLIC templates. This model posits an intersubunit site for anesthetic binding that may communicate with the intrasubunit region of each TMD. 

  • 20.
    Bertaccini, Edward J
    et al.
    Stanford University.
    Wallner, Björn
    Stockholm University.
    Trudell, James R
    Stanford University.
    Lindahl, Erik
    Stockholm University.
    Modeling anesthetic binding sites within the glycine alpha one receptor based on prokaryotic ion channel templates: the problem with TM42010In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 50, no 12, p. 2248-2255Article in journal (Refereed)
    Abstract [en]

    Ligand-gated ion channels (LGICs) significantly modulate anesthetic effects. Their exact molecular structure remains unknown. This has led to ambiguity regarding the proper amino acid alignment within their 3D structure and, in turn, the location of any anesthetic binding sites. Current controversies suggest that such a site could be located in either an intra- or intersubunit locale within the transmembrane domain of the protein. Here, we built a model of the glycine alpha one receptor (GlyRa1) based on the open-state structures of two new high-resolution ion channel templates from the prokaryote, Gloebacter violaceus (GLIC). Sequence scoring suggests reasonable homology between GlyRa1 and GLIC. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3): (ILE229, SER 267, and ALA 288). They line an intersubunit interface, in contrast to previous models. However, residues from the fourth transmembrane domain (TM4) that are known to modulate a variety of anesthetic effects are quite distant from this putative anesthetic binding site. While this model can account for a large proportion of the physicochemical data regarding such proteins, it cannot readily account for the alterations on anesthetic effects that are due to mutations within TM4.

  • 21.
    Bertaccini, Edward
    et al.
    Stanford University.
    Trudell, James
    Stanford University.
    Lindahl, Erik
    Stockholm University.
    Successful Calculation of Glycine Receptor Gating Motion Via a Full Molecular Mechanics Force Field2006Conference paper (Refereed)
    Abstract [en]

    Introduction: Analyses of ligand-gated ion channel receptors (LGIC) have demonstrated that possible sites of anesthetic action exist within their transmembrane domains. We have previously used molecular modeling techniques combined with experimental data to visualize a plausible model of an anesthetic binding site within a LGIC complex.1 We have also previously shown an approximate computational mechanism, based on an elastic network model, by which these ion channels may open and close and postulated how this motion may be affected by the presence of anesthetics.2 The difficulties with these approximation methods, however, lay in their inability to account for the modest effects of a separate ligand or a small mutation on ion channel motion. Here we show the successful application of a formal molecular mechanics force field for the normal mode calculation of protein motions.Methods: Coordinates of the homomeric GABARa1 pentamer complex composed of both an extracellular ligand binding domain and a transmembrane domain came from our previous work.3 Using this structure as a template, we built a model of the glyRa1 homomer using the homology modeling tools within the InsightII 2005 software package (Accelrys, San Diego, CA). This model then underwent a series of restrained optimizations within the GROMACS modeling package using the OPLS force field and no distance cutoffs on electrostatic and van der Waals interactions. After final unrestrained optimization, normal mode analysis was performed with a sparse matrix implementation.Results: As we previously reported for the approximate elastic network technique2, analysis of the entire glyRa1 complex demonstrated a clear iris-like motion of the protein about the central axis of the ion pore as the first (highest amplitude-lowest frequency) normal mode. In this mode, the rotation of the ligand binding domain occurred in the opposite direction to that of the transmembrane domain, producing a “wringing” like motion of the entire protein complex as it traversed its gating cycle. However, unlike the elastic network calculation of normal modes, which could only report relative frequencies of vibration, the GROMACS-based normal mode analysis allows for the calculation of real vibrational frequencies on the order of 321 GHz or around 3.1 ps per cycle. Likewise, while elastic network calculations could be completed in a few hours, the GROMACS calculations took approximately a week to complete on a Dell Workstation with dual 3GHz Xeon processors and a 64 bit software implementation.Conclusions: Despite these proteins containing upwards of 26,000 atoms, our new methods have made it possible to derive normal modes via the full implementation of a formal force field calculation. Despite their length and markedly increased complexity, these calculations still demonstrate that the harmonic motion of LGIC complexes is consistent with the direction of channel opening and closing. Such calculations should now allow the elucidation of the subtle effects on ion channel motion that are due to anesthetic binding.

  • 22.
    Bjelkmar, Pär
    et al.
    Stockholm University.
    Larsson, Per
    Cuendet, Michel
    EPFL Lausanne.
    Lindahl, Erik
    Stockholm University.
    Implementation of the CHARMM force field in GROMACS: Analysis of protein stability effects from correction maps, virtual interaction sites, and water models2010In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, no 2, p. 459-466Article in journal (Refereed)
    Abstract [en]

    CHARMM27 is a widespread and popular force field for biomolecular simulation, and several recent algorithms such as implicit solvent models have been developed specifically for it. We have here implemented the CHARMM force field and all necessary extended functional forms in the GROMACS molecular simulation package, to make CHARMM-specific features available and to test them in combination with techniques for extended time steps, to make all major force fields available for comparison studies in GROMACS, and to test various solvent model optimizations, in particular the effect of Lennard-Jones interactions on hydrogens. The implementation has full support both for CHARMM-specific features such as multiple potentials over the same dihedral angle and the grid-based energy correction map on the phi, psi protein backbone dihedrals, as well as all GROMACS features such as virtual hydrogen interaction sites that enable 5 fs time steps. The medium-to-long time effects of both the correction maps and virtual sites have been tested by performing a series of 100 ns simulations using different models for water representation, including comparisons between CHARMM and traditional TIP3P. Including the correction maps improves sampling of near native-state conformations in our systems, and to some extent it is even able to refine distorted protein conformations. Finally, we show that this accuracy is largely maintained with a new implicit solvent implementation that works with virtual interaction sites, which enables performance in excess of 250 ns/day for a 900-atom protein on a quad-core desktop computer.

  • 23.
    Bjelkmar, Pär
    et al.
    Stockholm University.
    Niemelä, Perttu S
    Helsinki University of Technology.
    Vattulainen, Ilpo
    Helsinki University of Technology.
    Lindahl, Erik
    Stockholm University.
    Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel2009In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 5, no 2, p. e1000289-Article in journal (Refereed)
    Abstract [en]

    Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.

  • 24.
    Blau, Christian
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Yvonnesdotter, Linnea
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Gentle and fast all-atom model refinement to cryo-EM densities via a maximum likelihood approach2023In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 19, no 7, p. e1011255-, article id e1011255Article in journal (Refereed)
    Abstract [en]

    Better detectors and automated data collection have generated a flood of high-resolution cryo-EM maps, which in turn has renewed interest in improving methods for determining structure models corresponding to these maps. However, automatically fitting atoms to densities becomes difficult as their resolution increases and the refinement potential has a vast number of local minima. In practice, the problem becomes even more complex when one also wants to achieve a balance between a good fit of atom positions to the map, while also establishing good stereochemistry or allowing protein secondary structure to change during fitting. Here, we present a solution to this challenge using a maximum likelihood approach by formulating the problem as identifying the structure most likely to have produced the observed density map. This allows us to derive new types of smooth refinement potential-based on relative entropy-in combination with a novel adaptive force scaling algorithm to allow balancing of force-field and density-based potentials. In a low-noise scenario, as expected from modern cryo-EM data, the relative-entropy based refinement potential outperforms alternatives, and the adaptive force scaling appears to aid all existing refinement potentials. The method is available as a component in the GROMACS molecular simulation toolkit. Author summaryCryo-electron microscopy has gone through a revolution and now regularly produces data with 2 & ANGS; resolution. However, this data comes in the shape of density maps, and fitting atomic coordinates into these maps can be a labor-intensive and challenging problem. This is particularly valid when there are multiple conformations, flexible regions, or parts of the structure with lower resolution. In many cases it is also desirable to to understand how a molecule moves between such conformations. This can be addressed with molecular dynamics simulations using densities as target restraints, but the refinement potentials commonly used can distort protein structure or get stuck in local minima when the cryo-EM map has high resolution. This work derives new refinement potentials based on models of the cryo-EM scattering process that provide a gentle way to fit protein structures to densities in simulations, and we also suggest an automated heuristic way to balance the influence of the map and simulation force field.

  • 25.
    Bondarenko, Vasyl
    et al.
    Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
    Chen, Qiang
    Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
    Singewald, Kevin
    Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
    Haloi, Nandan
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Tillman, Tommy S.
    Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
    Howard, Rebecca
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Xu, Yan
    Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
    Tang, Pei
    Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
    Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization2023In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, no 6, p. 1156-1165Article in journal (Refereed)
    Abstract [en]

    The α7 nicotinic acetylcholine receptor (α7nAChR) mediates signaling in the central nervous system and cholinergic anti-inflammatory pathways. Ivermectin is a positive allosteric modulator of a full-length α7nAChR and an agonist of the α7nAChR construct containing transmembrane (TMD) and intracellular (ICD) domains, but structural insights of the binding have not previously been determined. Here, combining nuclear magnetic resonance as a primary experimental tool with Rosetta comparative modeling and molecular dynamics simulations, we have revealed details of ivermectin binding to the α7nAChR TMD + ICD and corresponding structural changes in an ivermectin-induced desensitized state. Ivermectin binding was stabilized predominantly by hydrophobic interactions from interfacial residues between adjacent subunits near the extracellular end of the TMD, where the inter-subunit gap was substantially expanded in comparison to the apo structure. The ion-permeation pathway showed a profile distinctly different from the resting-state profile but similar to profiles of desensitized α7nAChR. The ICD also exhibited structural changes, including reorientation of the MX and h3 helices relative to the channel axis. The resulting structures of the α7nAChR TMD + ICD in complex with ivermectin provide opportunities for discovering new modulators of therapeutic potential and exploring the structural basis of cytoplasmic signaling under different α7nAChR functional states.

  • 26.
    Bondarenko, Vasyl
    et al.
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA..
    Wells, Marta M.
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA..
    Chen, Qiang
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA..
    Tillman, Tommy S.
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA..
    Singewald, Kevin
    Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA..
    Lawless, Matthew J.
    Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA..
    Caporoso, Joel
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA..
    Brandon, Nicole
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA..
    Coleman, Jonathan A.
    Univ Pittsburgh, Dept Struct Biol, Pittsburgh, PA 15260 USA..
    Saxena, Sunil
    Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Xu, Yan
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Struct Biol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Phys & Astron, Pittsburgh, PA 15260 USA..
    Tang, Pei
    Univ Pittsburgh, Dept Anesthesiol & Perioperat Med, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA..
    Structures of highly flexible intracellular domain of human alpha 7 nicotinic acetylcholine receptor2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 793Article in journal (Refereed)
    Abstract [en]

    The intracellular domain (ICD) of Cys-loop receptors mediates diverse functions. To date, no structure of a full-length ICD is available due to challenges stemming from its dynamic nature. Here, combining nuclear magnetic resonance (NMR) and electron spin resonance experiments with Rosetta computations, we determine full-length ICD structures of the human alpha 7 nicotinic acetylcholine receptor in a resting state. We show that similar to 57% of the ICD residues are in highly flexible regions, primarily in a large loop (loop L) with the most mobile segment spanning similar to 50 angstrom from the central channel axis. Loop L is anchored onto the MA helix and virtually forms two smaller loops, thereby increasing its stability. Previously known motifs for cytoplasmic binding, regulation, and signaling are found in both the helices and disordered flexible regions, supporting the essential role of the ICD conformational plasticity in orchestrating a broad range of biological processes.

  • 27.
    Brömstrup, Torben
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Howard, Rebecca J.
    Trudell, James R.
    Harris, R. Adron
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Inhibition versus Potentiation of Ligand-Gated Ion Channels Can Be Altered by a Single Mutation that Moves Ligands between Intra- and Intersubunit Sites2013In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 21, no 8, p. 1307-1316Article in journal (Refereed)
    Abstract [en]

    Pentameric ligand-gated ion channels (pLGICs) are similar in structure but either inhibited or potentiated by alcohols and anesthetics. This dual modulation has previously not been understood, but the determination of X-ray structures of prokaryotic GLIC provides an ideal model system. Here, we show that a single-site mutation at the F14' site in the GLIC transmembrane domain turns desflurane and chloroform from inhibitors to potentiators, and that this is explained by competing allosteric sites. The F14'A mutation opens an intersubunit site lined by N239 (15'), 1240 (16'), and Y263. Free energy calculations confirm this site is the preferred binding location for desflurane and chloroform in GLIC F14'A. In contrast, both anesthetics prefer an intrasubunit site in wild-type GLIC. Modulation is therefore the net effect of competitive binding between the intersubunit potentiating site and an intrasubunit inhibitory site. This provides direct evidence for a dual-site model of allosteric regulation of pLGICs.

  • 28.
    Brömstrup, Torben
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. Inst Pasteur, Grp Recepteurs Canaux, France.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Single-site mutation changes the location of the most favored Desflurane binding site in the GLIC ligand-gated ion channel2012In: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 243Article in journal (Other academic)
  • 29. Conti, Luca
    et al.
    Renhorn, Jakob
    Gabrielsson, Anders
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Turesson, Fredrik
    Liin, Sara I.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. Stockholm University, Sweden.
    Elinder, Fredrik
    Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 27562Article in journal (Refereed)
    Abstract [en]

    Voltage-gated potassium channels open at depolarized membrane voltages. A prolonged depolarization causes a rearrangement of the selectivity filter which terminates the conduction of ions - a process called slow or C-type inactivation. How structural rearrangements in the voltage-sensor domain (VSD) cause alteration in the selectivity filter, and vice versa, are not fully understood. We show that pulling the pore domain of the Shaker potassium channel towards the VSD by a Cd2+ bridge accelerates C-type inactivation. Molecular dynamics simulations show that such pulling widens the selectivity filter and disrupts the K+ coordination, a hallmark for C-type inactivation. An engineered Cd2+ bridge within the VSD also affect C-type inactivation. Conversely, a pore domain mutation affects VSD gating-charge movement. Finally, C-type inactivation is caused by the concerted action of distant amino acid residues in the pore domain. All together, these data suggest a reciprocal communication between the pore domain and the VSD in the extracellular portion of the channel.

  • 30. Conti, Luca
    et al.
    Renhorn, Jakob
    Gabrielsson, Anders
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Turesson, Fredrik
    Liin, Sara
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Elinder, Fredrik
    A Reciprocal Voltage Sensor-To-Pore Coupling in C-Type Inactivation2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 104A-104AArticle in journal (Other academic)
  • 31.
    Contreras, F.-Xabier
    et al.
    Heidelberg University.
    Ernst, Andreas M
    Heidelberg University.
    Haberkant, Per
    Heidelberg University.
    Björkholm, Patrik
    Stockholm University.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Gönen, Başak
    Tischer, Christian
    Heidelberg University.
    Elofsson, Arne
    Stockholm University.
    von Heijne, Gunnar
    Stockholm University.
    Thiele, Christoph
    Heidelberg University.
    Pepperkok, Rainer
    Heidelberg University.
    Wieland, Felix
    Heidelberg University.
    Brügger, Britta
    Heidelberg University.
    Molecular recognition of a single sphingolipid species by a protein's transmembrane domain2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 481, no 7382, p. 525-529Article in journal (Refereed)
    Abstract [en]

    Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

  • 32.
    Cowgill, John
    et al.
    Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 17121 Solna, Sweden.
    Fan, Chen
    Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 17121 Solna, Sweden.
    Haloi, Nandan
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tobiasson, Victor
    Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 17121 Solna, Sweden.
    Zhuang, Yuxuan
    Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 17121 Solna, Sweden.
    Howard, Rebecca J.
    Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 17121 Solna, Sweden.
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Structure and dynamics of differential ligand binding in the human ρ-type GABAA receptor2023In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 111, no 21, p. 5-3450Article in journal (Refereed)
    Abstract [en]

    The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of ρ-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.

  • 33.
    de la Rosa-Trevin, Jose Miguel
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Viga, Pedro Alberto Hernandez
    UNEAC Manzanillo, Manzanillo, Cuba..
    Oton, Joaquin
    MRC, Lab Mol Biol, Cambridge, England..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Development of basic building blocks for cryo-EM: the emcore and emvis software libraries2020In: Acta Crystallographica Section D: Structural Biology , E-ISSN 2059-7983, Vol. 76, p. 350-356Article in journal (Refereed)
    Abstract [en]

    Image-processing software has always been an integral part of structure determination by cryogenic electron microscopy (cryo-EM). Recent advances in hardware and software are recognized as one of the key factors in the so-called cryo-EM resolution revolution. Increasing computational power has opened many possibilities to consider more demanding algorithms, which in turn allow more complex biological problems to be tackled. Moreover, data processing has become more accessible to many experimental groups, with computations that used to last for many days at supercomputing facilities now being performed in hours on personal workstations. All of these advances, together with the rapid expansion of the community, continue to pose challenges and new demands on the software-development side. In this article, the development of emcore and emvis, two basic software libraries for image manipulation and data visualization in cryo-EM, is presented. The main goal is to provide basic functionality organized in modular components that other developers can reuse to implement new algorithms or build graphical applications. An additional aim is to showcase the importance of following established practices in software engineering, with the hope that this could be a first step towards a more standardized way of developing and distributing software in the field.

  • 34.
    Elofsson, Arne
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Hess, Berk
    KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Onufriev, Alexey
    Virginia Tech, Dept Comp Sci, Ctr Soft Matter & Biol Phys, Blacksburg, VA USA.;Virginia Tech, Dept Phys, Ctr Soft Matter & Biol Phys, Blacksburg, VA USA..
    van der Spoel, David
    Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, Uppsala Ctr Computat Chem, Uppsala, Sweden..
    Wallqvist, Anders
    US Army Med Res & Mat Command, Dept Def Biotechnol High Performance Comp Softwar, Telemed & Adv Technol Res Ctr, Ft Detrick, MD USA..
    Ten simple rules on how to create open access and reproducible molecular simulations of biological systems2019In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, no 1, article id e1006649Article in journal (Other academic)
  • 35.
    Eriksson, Olivia
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Laure, Erwin
    KTH, School of Electrical Engineering and Computer Science (EECS), Centres, Centre for High Performance Computing, PDC. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Henningson, Dan S.
    KTH, School of Engineering Sciences (SCI), Mechanics, Stability, Transition and Control. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Ynnerman, Anders
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, SeRC - Swedish e-Science Research Centre.
    e-Science in Scandinavia2018In: Informatik-Spektrum, ISSN 0170-6012, E-ISSN 1432-122X, Vol. 41, no 6, p. 398-404Article in journal (Refereed)
  • 36. Facey, Jody-Ann
    et al.
    Venner, Laura
    Hyde, Michael
    Pouya, Iman
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Howard, Rebecca
    Polar substitutions in the ion-conducting pore of GLIC alter gating and alcohol modulation2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, p. 1061.9-Article in journal (Other academic)
  • 37.
    Fan, Chen
    et al.
    Stockholm Univ, Stockholm, Sweden..
    Legesse, Dagimhiwat
    UT Southwestern Med Ctr, Dallas, TX USA..
    Zhuang, Yuxuan
    Stockholm Univ, Stockholm, Sweden..
    Noviello, Colleen
    UT Southwestern Med Ctr, Dallas, TX USA..
    Hibbs, Ryan
    UT Southwestern Med Ctr, Dallas, TX USA..
    Howard, Reba
    Stockholm Univ, Stockholm, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Stockholm, Sweden..
    Structural insights into opposing actions of neurosteroids on GABAA receptors2023In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 52, no SUPPL 1, p. S129-S129Article in journal (Other academic)
  • 38. Forsberg, Björn
    et al.
    Aibara, Shintaro
    Howard, R. J.
    Mortezaei, N.
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Arrangement and symmetry of the fungal E3BP-containing core of the pyruvate dehydrogenase complex2020In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 4667Article in journal (Refereed)
    Abstract [en]

    The pyruvate dehydrogenase complex (PDC) is a multienzyme complex central to aerobic respiration, connecting glycolysis to mitochondrial oxidation of pyruvate. Similar to the E3-binding protein (E3BP) of mammalian PDC, PX selectively recruits E3 to the fungal PDC, but its divergent sequence suggests a distinct structural mechanism. Here, we report reconstructions of PDC from the filamentous fungus Neurospora crassa by cryo-electron microscopy, where we find protein X (PX) interior to the PDC core as opposed to substituting E2 core subunits as in mammals. Steric occlusion limits PX binding, resulting in predominantly tetrahedral symmetry, explaining previous observations in Saccharomyces cerevisiae. The PX-binding site is conserved in (and specific to) fungi, and complements possible C-terminal binding motifs in PX that are absent in mammalian E3BP. Consideration of multiple symmetries thus reveals a differential structural basis for E3BP-like function in fungal PDC.

  • 39.
    Fourati, Zaineb
    et al.
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Heusser, Stephanie A.
    Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Hu, Haidai
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France.;UPMC Univ Paris 6, Sorbonne Univ, F-75005 Paris, France..
    Ruza, Reinis R.
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Sauguet, Ludovic
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.
    Delarue, Marc
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels2018In: Cell Reports, E-ISSN 2211-1247, Vol. 23, no 4, p. 993-1004Article in journal (Refereed)
    Abstract [en]

    Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

  • 40.
    Gabrielsson, Anders
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Liin, Sara
    Elinder, Fredrik
    Lindahl, Erik
    Binding Structure & Dynamics for Toxins Modifying the Gating Mechanism of Kv Channels2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 738A-738AArticle in journal (Other academic)
  • 41.
    Gharpure, Anant
    et al.
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA..
    Teng, Jinfeng
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA..
    Zhuang, Yuxuan
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-17121 Solna, Sweden..
    Noviello, Colleen M.
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA..
    Walsh, Richard M., Jr.
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA.;Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA..
    Cabuco, Rico
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-17121 Solna, Sweden..
    Zaveri, Nurulain T.
    Astraea Therapeut, Mountain View, CA 94043 USA..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Hibbs, Ryan E.
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA..
    Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor2019In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 104, no 3, p. 501-+Article in journal (Refereed)
    Abstract [en]

    Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.

  • 42.
    Gomez-Blanco, J.
    et al.
    McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada..
    de la Rosa-Trevin, J. M.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Marabini, R.
    Univ Autonoma Madrid, Escuela Politecn Super, E-28049 Madrid, Spain..
    del Cano, L.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Jimenez, A.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Martinez, M.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Melero, R.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Majtner, T.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Maluenda, D.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Mota, J.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Rancel, Y.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Ramirez-Aportela, E.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Vilas, J. L.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Carroni, M.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Fleischmann, S.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.;KTH Royal Inst Technol, Swedish E Sci Res Ctr, Stockholm, Sweden..
    Ashton, A. W.
    Harwell Sci & Innovat Campus, Diamond Light Source, Didcot OX11 0DE, Oxon, England..
    Basham, M.
    Harwell Sci & Innovat Campus, Diamond Light Source, Didcot OX11 0DE, Oxon, England..
    Clare, D. K.
    Harwell Sci & Innovat Campus, Diamond Light Source, Didcot OX11 0DE, Oxon, England..
    Savage, K.
    Harwell Sci & Innovat Campus, Diamond Light Source, Didcot OX11 0DE, Oxon, England..
    Siebert, C. A.
    Harwell Sci & Innovat Campus, Diamond Light Source, Didcot OX11 0DE, Oxon, England..
    Sharov, G. G.
    MRC, Lab Mol Biol, Francis Crick Ave, Cambridge CB2 OQH, England..
    Sorzano, C. O. S.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Conesa, P.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Carazo, J. M.
    CSIC, Natl Ctr Biotechnol, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain..
    Using Scipion for stream image processing at Cryo-EM facilities2018In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 204, no 3, p. 457-463Article in journal (Refereed)
    Abstract [en]

    Three dimensional electron microscopy is becoming a very data-intensive field in which vast amounts of experimental images are acquired at high speed. To manage such large-scale projects, we had previously developed a modular workflow system called Scipion (de la Rosa-Trevfn et al., 2016). We present here a major extension of Scipion that allows processing of EM images while the data is being acquired. This approach helps to detect problems at early stages, saves computing time and provides users with a detailed evaluation of the data quality before the acquisition is finished. At present, Scipion has been deployed and is in production mode in seven Cryo-EM facilities throughout the world.

  • 43.
    Gossen, Jonas
    et al.
    Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany..
    Albani, Simone
    Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany..
    Hanke, Anton
    Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany.;Heidelberg Univ, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany..
    Joseph, Benjamin P.
    Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany..
    Bergh, Cathrine
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kuzikov, Maria
    Fraunhofer Inst Translat Med & Pharmacol ITMP, Dept Screening Port, D-22525 Hamburg, Germany..
    Costanzi, Elisa
    Elettra Sincrotrone Trieste SCpA, I-34149 Trieste, Italy..
    Manelfi, Candida
    Dompe Farmaceut SpA, I-67100 Laquila, Italy..
    Storici, Paola
    Elettra Sincrotrone Trieste SCpA, I-34149 Trieste, Italy..
    Gribbon, Philip
    Fraunhofer Inst Translat Med & Pharmacol ITMP, Dept Screening Port, D-22525 Hamburg, Germany..
    Beccari, Andrea R.
    Dompe Farmaceut SpA, I-67100 Laquila, Italy..
    Talarico, Carmine
    Dompe Farmaceut SpA, I-67100 Laquila, Italy..
    Spyrakis, Francesca
    Univ Turin, Dept Drug Sci & Technol, I-10125 Turin, Italy..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zaliani, Andrea
    Fraunhofer Inst Translat Med & Pharmacol ITMP, Dept Screening Port, D-22525 Hamburg, Germany..
    Carloni, Paolo
    Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany..
    Wade, Rebecca C.
    Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany.;Heidelberg Univ, Zentrum Molekulare Biol, DKTZ ZMBH Alliance, D-69120 Heidelberg, Germany.;Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, D-69120 Heidelberg, Germany..
    Musiani, Francesco
    Univ Bologna, Lab Bioinorgan Chem, Dept Pharm & Biotechnol, I-40126 Bologna, Italy..
    Kokh, Daria B.
    Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany..
    Rossetti, Giulia
    Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Forschungszentrum Julich, Julich Supercomp Ctr JSC, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Dept Hematol Oncol Hemostaseol & Stem Cell Transp, D-44517 Aachen, Germany..
    A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics2021In: ACS Pharmacology & Translational Science, E-ISSN 2575-9108, Vol. 4, no 3, p. 1079-1095Article in journal (Refereed)
    Abstract [en]

    The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of similar to 30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing similar to 200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.

  • 44.
    Haloi, Nandan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH Royal Inst Technol, Stockholm, Sweden..
    Howard, Rebecca
    Stockholm Univ, Stockholm, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Stockholm, Sweden..
    Structural and energetic characterizations of the conformational landscapes in ligand gated ion channels using adaptive sampling and Markov state modeling2023In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 52, no SUPPL 1, p. S60-S60Article in journal (Other academic)
  • 45.
    Haloi, Nandan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Huang, Shan
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Nichols, Aaron L.
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Fine, Eve J.
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Friesenhahn, Nicholas J.
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Marotta, Christopher B.
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Dougherty, Dennis A.
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Howard, Rebecca J.
    Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm 10691, Sweden.
    Mayo, Stephen L.
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Lester, Henry A.
    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
    Interactive computational and experimental approaches improve the sensitivity of periplasmic binding protein-based nicotine biosensors for measurements in biofluids2024In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 37, article id gzae003Article in journal (Refereed)
    Abstract [en]

    We developed fluorescent protein sensors for nicotine with improved sensitivity. For iNicSnFR12 at pH 7.4, the proportionality constant for ∆F/F0 vs [nicotine] (δ-slope, 2.7 μM−1) is 6.1-fold higher than the previously reported iNicSnFR3a. The activated state of iNicSnFR12 has a fluorescence quantum yield of at least 0.6. We measured similar dose-response relations for the nicotine-induced absorbance increase and fluorescence increase, suggesting that the absorbance increase leads to the fluorescence increase via the previously described nicotine-induced conformational change, the ‘candle snuffer’ mechanism. Molecular dynamics (MD) simulations identified a binding pose for nicotine, previously indeterminate from experimental data. MD simulations also showed that Helix 4 of the periplasmic binding protein (PBP) domain appears tilted in iNicSnFR12 relative to iNicSnFR3a, likely altering allosteric network(s) that link the ligand binding site to the fluorophore. In thermal melt experiments, nicotine stabilized the PBP of the tested iNicSnFR variants. iNicSnFR12 resolved nicotine in diluted mouse and human serum at 100 nM, the peak [nicotine] that occurs during smoking or vaping, and possibly at the decreasing levels during intervals between sessions. NicSnFR12 was also partially activated by unidentified endogenous ligand(s) in biofluids. Improved iNicSnFR12 variants could become the molecular sensors in continuous nicotine monitors for animal and human biofluids.

  • 46.
    Hennerdal, Aron
    et al.
    Stockholm University.
    Falk, Jenny
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Elofsson, Arne
    Stockholm University.
    Internal duplications in α-helical membrane protein topologies are common but the nonduplicated forms are rare.2010In: Protein science : a publication of the Protein Society, ISSN 1469-896X, Vol. 19, no 12, p. 2305-18Article in journal (Refereed)
    Abstract [en]

    Many α-helical membrane proteins contain internal symmetries, indicating that they might have evolved through a gene duplication and fusion event. Here, we have characterized internal duplications among membrane proteins of known structure and in three complete genomes. We found that the majority of large transmembrane (TM) proteins contain an internal duplication. The duplications found showed a large variability both in the number of TM-segments included and in their orientation. Surprisingly, an approximately equal number of antiparallel duplications and parallel duplications were found. However, of all 11 superfamilies with an internal duplication, only for one, the AcrB Multidrug Efflux Pump, the duplicated unit could be found in its nonduplicated form. An evolutionary analysis of the AcrB homologs indicates that several independent fusions have occurred, including the fusion of the SecD and SecF proteins into the 12-TM-protein SecDF in Brucella and Staphylococcus aureus. In one additional case, the Vitamin B12 transporter-like ABC transporters, the protein had undergone an additional fusion to form protein with 20 TM-helices in several bacterial genomes. Finally, homologs to all human membrane proteins were used to detect the presence of duplicated and nonduplicated proteins. This confirmed that only in rare cases can homologs with different duplication status be found, although internal symmetry is frequent among these proteins. One possible explanation is that it is frequent that duplication and fusion events happen simultaneously and that there is almost always a strong selective advantage for the fused form.

  • 47. Henrion, Ulrike
    et al.
    Renhorn, Jakob
    Börjesson, Sara I.
    Nelson, Erin M.
    Schwaiger, Christine S.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Bjelkmar, Pär
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Wallner, Björn
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Elinder, Fredrik
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8552-8557Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

  • 48.
    Hess, Berk
    et al.
    Max-Planck Institut Mainz.
    Kutzner, Carsten
    Max-Planck Institut Göttingen.
    van der Spoel, David
    Uppsala University.
    Lindahl, Erik
    Stockholm University.
    GROMACS 4.0: Algorithms for highly efficient, load balanced, and scalable molecular simulation2008In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, no 2, p. 435-Article in journal (Refereed)
    Abstract [en]

    Molecular simulation is an extremely useful, but computationally very expensive tool for studies of chemical and biomolecular systems. Here, we present a new implementation of our molecular simulation toolkit GROMACS which now both achieves extremely high performance on single processors from algorithmic optimizations and hand-coded routines and simultaneously scales very well on parallel machines. The code encompasses a minimal-communication domain decomposition algorithm, full dynamic load balancing, a state-of-the-art parallel constraint solver, and efficient virtual site algorithms that allow removal of hydrogen atom degrees of freedom to enable integration time steps up to 5 fs; for atomistic simulations also in parallel. To improve the scaling properties of the common particle mesh Ewald electrostatics algorithms, we have in addition used a Multiple-Program, Multiple-Data approach, with separate node domains responsible for direct and reciprocal space interactions. Not only does this combination of algorithms enable extremely long simulations of large systems but also it provides that simulation performance on quite modest numbers of standard cluster nodes.

  • 49. Heusser, Stephanie A.
    et al.
    Howard, Rebecca J.
    Borghese, Cecilia M.
    Cullins, Madeline A.
    Brömstrup, Torben
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Ui S.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Carlsson, Jens
    Harris, R. Adron
    Functional Validation of Virtual Screening for Novel Agents with General Anesthetic Action at Ligand-Gated Ion Channelss2013In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 84, no 5, p. 670-678Article in journal (Refereed)
    Abstract [en]

    GABA(A) receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABA(A) receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC. In total, 29 compounds were selected for functional testing on recombinant GLIC, and 16 of these compounds modulated GLIC function. Active compounds were also tested on recombinant GABA(A) receptors, and point mutations around the presumed binding pocket were introduced into GLIC and GABA(A) receptors to test for binding specificity. The potency of active compounds was only weakly correlated with properties such as lipophilicity or molecular weight. One compound was found to mimic the actions of propofol on GLIC and GABA(A), and to be sensitive to mutations that reduce the action of propofol in both receptors. Mutant receptors also provided insight about the position of the binding sites and the relevance of the receptor's conformation for anesthetic actions. Overall, the findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel GABA(A) receptor ligands.

  • 50. Heusser, Stephanie A.
    et al.
    Howard, Rebecca J.
    Pouya, Iman
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Klement, Göran
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Borghese, Cecilia
    Harris, R. Adron
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholms universitet.
    A Single Mutation in GLIC Reveals Both the Potentiating and the Inhibitory Nature of Propofol2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 456A-456AArticle in journal (Other academic)
1234 1 - 50 of 186
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