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  • 1.
    Abraham, Mark James
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    Murtola, Teemu
    Schulz, Roland
    Pall, Szilard
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    Smith, Jeremy C.
    Hess, Berk
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    Lindahl, Erik
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers2015Inngår i: SoftwareX, E-ISSN 2352-7110, Vol. 1-2, s. 19-25Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 2.
    Aman, Ken
    et al.
    Umeå University.
    Lindahl, Erik
    KTH, Tidigare Institutioner, Fysik.
    Edholm, Olle
    KTH, Tidigare Institutioner, Fysik.
    Håkansson, Pär
    Umeå University.
    Westlund, Per-Olof
    Umeå University.
    Structure and dynamics of interfacial water in an Lalpha phase lipid bilayer from molecular dynamics simulations.2003Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, nr 1, s. 102-15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Based on molecular dynamics simulations, an analysis of structure and dynamics is performed on interfacial water at a liquid crystalline dipalmitoylphosphatidycholine/water system. Water properties relevant for understanding NMR relaxation are emphasized. The first and second rank orientational order parameters of the water O-H bonds were calculated, where the second rank order parameter is in agreement with experimental determined quadrupolar splittings. Also, two different interfacial water regions (bound water regions) are revealed with respect to different signs of the second rank order parameter. The water reorientation correlation function reveals a mixture of fast and slow decaying parts. The fast (ps) part of the correlation function is due to local anisotropic water reorientation whereas the much slower part is due to more complicated processes including lateral diffusion along the interface and chemical exchange between free and bound water molecules. The 100-ns-long molecular dynamics simulation at constant pressure (1 atm) and at a temperature of 50 degrees C of 64 lipid molecules and 64 x 23 water molecules lack a slow water reorientation correlation component in the ns time scale. The (2)H(2)O powder spectrum of the dipalmitoylphosphatidycholine/water system is narrow and consequently, the NMR relaxation time T(2) is too short compared to experimental results.

  • 3.
    Andersson, Magnus
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik.
    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 Permease2015Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, nr 2, s. 309A-309AArtikkel i tidsskrift (Annet vitenskapelig)
  • 4.
    Andersson, Magnus
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mattle, Daniel
    Sitsel, Oleg
    Nielsen, Anna Marie
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Experimentell biomolekylär fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    White, Stephen H.
    Nissen, Poul
    Gourdon, Pontus
    Transport Pathway in Cu+ P-Type ATPases2014Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 2, s. 427A-427AArtikkel i tidsskrift (Annet vitenskapelig)
  • 5.
    Apostolov, Rossen
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Centra, Parallelldatorcentrum, PDC.
    Axner, Lilit
    KTH, Skolan för datavetenskap och kommunikation (CSC), Centra, Parallelldatorcentrum, PDC.
    Agren, Hans
    Ayugade, Eduard
    Duta, Mihai
    Gelpi, Jose Luis
    Gimenez, Judit
    Goni, Ramon
    Hess, Berk
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Jamitzky, Ferdinand
    Kranzmuller, Dieter
    Labarta, Jesus
    Laure, Erwin
    KTH, Skolan för datavetenskap och kommunikation (CSC), Centra, Parallelldatorcentrum, PDC.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Orozco, Modesto
    Peterson, Magnus
    Satzger, Helmut
    Trefethen, Anne
    Scalable Software Services for Life Science2011Inngår i: Proceedings of 9th HealthGrid conference, 2011Konferansepaper (Fagfellevurdert)
    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.

  • 6.
    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.2006Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 34, nr Web Server issue, s. W38-42Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7.
    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 principles2008Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 20, s. 7177-7781Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 8. Bertaccini, E. J.
    et al.
    Yoluk, Özge
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik R.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, 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 receptor2013Inngår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 119, nr 5, s. 1087-1095Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9.
    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 protein2008Inngår i: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 48, nr 4, s. 855-860Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 10.
    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 Channels2007Konferansepaper (Fagfellevurdert)
    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.

  • 11.
    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 methods2007Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 47, nr 4, s. 1572-1579Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 12.
    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 Membranes2008Konferansepaper (Fagfellevurdert)
    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.

  • 13.
    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 Templates2009Inngår i: Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists, 2009Konferansepaper (Fagfellevurdert)
    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. 

  • 14.
    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 TM42010Inngår i: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 50, nr 12, s. 2248-2255Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 15.
    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 Field2006Konferansepaper (Fagfellevurdert)
    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.

  • 16.
    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 models2010Inngår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, nr 2, s. 459-466Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 17.
    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 channel2009Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 5, nr 2, s. e1000289-Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 18.
    Brömstrup, Torben
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Howard, Rebecca J.
    Trudell, James R.
    Harris, R. Adron
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, 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 Sites2013Inngår i: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 21, nr 8, s. 1307-1316Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19.
    Brömstrup, Torben
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Murail, Samuel
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. Inst Pasteur, Grp Recepteurs Canaux, France.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Single-site mutation changes the location of the most favored Desflurane binding site in the GLIC ligand-gated ion channel2012Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 243Artikkel i tidsskrift (Annet vitenskapelig)
  • 20. Conti, Luca
    et al.
    Renhorn, Jakob
    Gabrielsson, Anders
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Turesson, Fredrik
    Liin, Sara I.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. Stockholm University, Sweden.
    Elinder, Fredrik
    Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 27562Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 21. Conti, Luca
    et al.
    Renhorn, Jakob
    Gabrielsson, Anders
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Turesson, Fredrik
    Liin, Sara
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Elinder, Fredrik
    A Reciprocal Voltage Sensor-To-Pore Coupling in C-Type Inactivation2016Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, nr 3, s. 104A-104AArtikkel i tidsskrift (Annet vitenskapelig)
  • 22.
    Contreras, F.-Xabier
    et al.
    Heidelberg University.
    Ernst, Andreas M
    Heidelberg University.
    Haberkant, Per
    Heidelberg University.
    Björkholm, Patrik
    Stockholm University.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    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 domain2012Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 481, nr 7382, s. 525-529Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23.
    Elofsson, Arne
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Hess, Berk
    KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, Centra, 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 systems2019Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 1, artikkel-id e1006649Artikkel i tidsskrift (Annet vitenskapelig)
  • 24.
    Eriksson, Olivia
    et al.
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
    Laure, Erwin
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Centra, Parallelldatorcentrum, PDC.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Henningson, Dan S.
    KTH, Skolan för teknikvetenskap (SCI), Mekanik, Stabilitet, Transition, Kontroll.
    Ynnerman, Anders
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
    e-Science in Scandinavia2018Inngår i: Informatik-Spektrum, ISSN 0170-6012, E-ISSN 1432-122X, Vol. 41, nr 6, s. 398-404Artikkel i tidsskrift (Fagfellevurdert)
  • 25. Facey, Jody-Ann
    et al.
    Venner, Laura
    Hyde, Michael
    Pouya, Iman
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Howard, Rebecca
    Polar substitutions in the ion-conducting pore of GLIC alter gating and alcohol modulation2014Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, nr 1, s. 1061.9-Artikkel i tidsskrift (Annet vitenskapelig)
  • 26.
    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, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, 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 Channels2018Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 23, nr 4, s. 993-1004Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 27.
    Gabrielsson, Anders
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Liin, Sara
    Elinder, Fredrik
    Lindahl, Erik
    Binding Structure & Dynamics for Toxins Modifying the Gating Mechanism of Kv Channels2014Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 2, s. 738A-738AArtikkel i tidsskrift (Annet vitenskapelig)
  • 28.
    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, Centra, 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 facilities2018Inngår i: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 204, nr 3, s. 457-463Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 29.
    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.2010Inngår i: Protein science : a publication of the Protein Society, ISSN 1469-896X, Vol. 19, nr 12, s. 2305-18Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 30. Henrion, Ulrike
    et al.
    Renhorn, Jakob
    Börjesson, Sara I.
    Nelson, Erin M.
    Schwaiger, Christine S.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Bjelkmar, Pär
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Wallner, Björn
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Elinder, Fredrik
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 22, s. 8552-8557Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 31.
    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 simulation2008Inngår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, nr 2, s. 435-Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 32. Heusser, Stephanie A.
    et al.
    Howard, Rebecca J.
    Borghese, Cecilia M.
    Cullins, Madeline A.
    Brömstrup, Torben
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Ui S.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, 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 Channelss2013Inngår i: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 84, nr 5, s. 670-678Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 33. Heusser, Stephanie A.
    et al.
    Howard, Rebecca J.
    Pouya, Iman
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Klement, Göran
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Borghese, Cecilia
    Harris, R. Adron
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. Stockholms universitet.
    A Single Mutation in GLIC Reveals Both the Potentiating and the Inhibitory Nature of Propofol2016Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, nr 3, s. 456A-456AArtikkel i tidsskrift (Annet vitenskapelig)
  • 34.
    Heusser, Stephanie A.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Lycksell, Marie
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Wang, Xueqing
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    McComas, Sarah E.
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Lindahl, Erik
    KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity2018Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 42, s. 10672-10677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to similar to 30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

  • 35.
    Heusser, Stephanie A.
    et al.
    SciLifeLab, Solna, Sweden.;Stockholm Univ, S-10691 Stockholm, Sweden..
    Yoluk, Ozge
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Exploring the Gating Pathway in an Eukaryotic Ligand-Gated Ion Channel2015Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, nr 2, s. 433A-433AArtikkel i tidsskrift (Annet vitenskapelig)
  • 36. Heusser, Stephanie
    et al.
    Yoluk, Özge
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Klement, Goran
    Reiderer, Erika
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Howard, Rebecca
    Functional Characterization of Neurotransmitter Activation and Modulation in a Nematode Model Ligand-gated Ion Channel2016Inngår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 138, nr 2, s. 243-253Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines and anticonvulsants. However, the mechanisms of ion channel opening, gating and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modifiedCaenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery.

  • 37.
    Hofsäss, Christofer
    et al.
    KTH, Tidigare Institutioner, Fysik.
    Lindahl, Erik
    KTH, Tidigare Institutioner, Fysik.
    Edholm, Olle
    KTH, Tidigare Institutioner, Fysik.
    Molecular dynamics simulations of phospholipid bilayers with cholesterol.2003Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, nr 4, s. 2192-206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To investigate the microscopic interactions between cholesterol and lipids in biological membranes, we have performed a series of molecular dynamics simulations of large membranes with different levels of cholesterol content. The simulations extend to 10 ns, and were performed with hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers. The bilayers contain 1024 lipids of which 0-40% were cholesterol and the rest DPPC. The effects of cholesterol on the structure and mesoscopic dynamics of the bilayer were monitored as a function of cholesterol concentration. The main effects observed are a significant ordering of the DPPC chains (as monitored by NMR type order parameters), a reduced fraction of gauche bonds, a reduced surface area per lipid, less undulations--corresponding to an increased bending modulus for the membrane, smaller area fluctuations, and a reduced lateral diffusion of DPPC-lipids as well as cholesterols.

  • 38.
    Howard, R. J.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Heusser, S. A.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Zhuang, Y.
    Uppsala Univ, Sect Chem, Uppsala, Sweden..
    Lycksell, M.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Klement, Göran
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Orellana, L.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS2018Inngår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, s. 60A-60AArtikkel i tidsskrift (Fagfellevurdert)
  • 39.
    Howard, Rebecca J.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Fourati, Zaineb
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Heusser, Stephanie A.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Hui, Haidai
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Ruza, Reinis R.
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Sauguet, Ludovic
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Fysik, Beräkningsbiofysik. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Delarue, Marc
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Structural Details of an Allosteric Mechanism for Bimodal Anesthetic Modulation of Pentameric Ligand-Gated Ion Channels2018Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, nr 3, s. 204A-204AArtikkel i tidsskrift (Annet vitenskapelig)
  • 40. Howard, Rebecca J.
    et al.
    Heusser, Stephanie A.
    Yoluk, Ozge
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik.
    Snow, Oliver
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik. Stockholm Univ, Sweden.
    Klement, Göran
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik. Stockholm Univ, Sweden.
    Mola, Alex R.
    Ruel, Travers M. D.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik. Stockholm Univ, Sweden.
    Transmembrane Structural Determinants of Alcohol Binding and Modulation in a Model Ligand-Gated Ion Channel2017Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, nr 3, s. 554A-554AArtikkel i tidsskrift (Fagfellevurdert)
  • 41. Howard, Rebecca J.
    et al.
    Murail, Samuel
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Broemstrup, Torben
    Horani, Suzzane
    Lee, Ui S.
    Ondricek, Kathryn E.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Bertaccini, Edward J.
    Trudell, James R.
    Harris, R. Adron
    Combined functional-computational approach to characterize sites of anesthetic modulation of ligand-gated ion channels2012Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 243Artikkel i tidsskrift (Annet vitenskapelig)
  • 42.
    Howard, Rebecca J
    et al.
    University of Texas.
    Murail, Samuel
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Ondricek, Kathryn E
    University of Texas.
    Corringer, Pierre-Jean
    Institut Pasteur.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Trudell, James R
    Stanford University.
    Harris, R Adron
    University of Texas.
    Structural basis for alcohol modulation of a pentameric ligand-gated ion channel2011Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 29, s. 12149-54Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the "linking tunnel." These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.

  • 43. Howard, Rebecca J.
    et al.
    Murail, Samuel
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Ondricek, Kathryn E.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Trudell, James R.
    Harris, R. Adron
    Structural Basis For Alcohol Modulation of Pentameric Ligand-Gated Ion Channels2012Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, nr 3, s. 411A-411AArtikkel i tidsskrift (Annet vitenskapelig)
  • 44. Howard, Rebecca J.
    et al.
    Sauguet, Ludovic
    Brömstrup, Torben
    Swedish e-Science Resarch Centre.
    Murail, Samuel
    Lee, Ui S.
    Horani, Suzzane
    Trudell, James R.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Delarue, Marc
    Harris, R. Adron
    Alcohol and Anesthetic Binding to Pentameric Ligand-Gated Ion Channels Revealed in a Prokaryotic Model System2013Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, nr 2, s. 635A-636AArtikkel i tidsskrift (Annet vitenskapelig)
  • 45.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Amino-acid solvation structure in transmembrane helices from molecular dynamics simulations.2006Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 91, nr 12, s. 4450-63Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Understanding the solvation of amino acids in biomembranes is an important step to better explain membrane protein folding. Several experimental studies have shown that polar residues are both common and important in transmembrane segments, which means they have to be solvated in the hydrophobic membrane, at least until helices have aggregated to form integral proteins. In this work, we have used computer simulations to unravel these interactions on the atomic level, and classify intramembrane solvation properties of amino acids. Simulations have been performed for systematic mutations in poly-Leu helices, including not only each amino acid type, but also every z-position in a model helix. Interestingly, many polar or charged residues do not desolvate completely, but rather retain hydration by snorkeling or pulling in water/headgroups--even to the extent where many of them exist in a microscopic polar environment, with hydration levels corresponding well to experimental hydrophobicity scales. This suggests that even for polar/charged residues a large part of solvation cost is due to entropy, not enthalpy loss. Both hydration level and hydrogen bonding exhibit clear position-dependence. Basic side chains cause much less membrane distortion than acidic, since they are able to form hydrogen bonds with carbonyl groups instead of water or headgroups. This preference is supported by sequence statistics, where basic residues have increased relative occurrence at carbonyl z-coordinates. Snorkeling effects and N-/C-terminal orientation bias are directly observed, which significantly reduces the effective thickness of the hydrophobic core. Aromatic side chains intercalate efficiently with lipid chains (improving Trp/Tyr anchoring to the interface) and Ser/Thr residues are stabilized by hydroxyl groups sharing hydrogen bonds to backbone oxygens.

  • 46.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Position-resolved free energy of solvation for amino acids in lipid membranes from molecular dynamics simulations.2008Inngår i: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 70, nr 4, s. 1332-44Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies of insertion and interactions of amino acids in lipid membranes are pivotal to our understanding of membrane protein structure and function. Calculating the insertion cost as a function of transmembrane helix sequence is thus an important step towards improved membrane protein prediction and eventually drug design. Here, we present position-dependent free energies of solvation for all amino acid analogs along the membrane normal. The profiles cover the entire region from bulk water to hydrophobic core, and were produced from all-atom molecular dynamics simulations. Experimental differences corresponding to mutations and costs for entire segments match experimental data well, and in addition the profiles provide the spatial resolution currently not available from experiments. Polar side-chains largely maintain their hydration and assume quite ordered conformations, which indicates the solvation cost is mainly entropic. The cost of solvating charged side-chains is not only significantly lower than for implicit solvation models, but also close to experiments, meaning these could well maintain their protonation states inside the membrane. The single notable exception to the experimental agreement is proline, which is quite expensive to introduce in vivo despite its hydrophobicity--a difference possibly explained by kinks making it harder to insert helices in the translocon.

  • 47.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Protein contents in biological membranes can explain abnormal solvation of charged and polar residues.2009Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 37, s. 15684-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transmembrane helices are generally believed to insert into membranes based on their hydrophobicity. Nevertheless, there are important exceptions where polar residues have great functional importance, for instance the S4 helix of voltage-gated ion channels. It has been shown experimentally that insertion can be accomplished by hydrophobic counterbalance, predicting an arginine insertion cost of only 2.5 kcal/mol, compared with 14.9 kcal/mol in cyclohexane. Previous simulations of pure bilayers have produced values close to the pure hydrocarbon, which has lead to spirited discussion about the experimental conditions. Here, we have performed computer simulations of models better mimicking biological membranes by explicitly including protein helices at mass fractions from 15% to 55%, as well as an actual translocon. This has a striking effect on the solvation free energy of arginine. With some polar residues present, the solvation cost comes close to experimental observation at approximately 30% mass fraction, and negligible at 40%. In the presence of a translocon in the membrane, the cost of inserting arginine next to the lateral gate can be as low as 3-5 kcal/mol. The effect is mainly due to the extra helices making it easier to retain hydration water. These results offer a possible explanation for the discrepancy between the in vivo hydrophobicity scale and computer simulations and highlight the importance of the high protein contents in membranes. Although many membrane proteins are stable in pure bilayers, such simplified models might not be sufficiently accurate for insertion of polar or charged residues in biological membranes.

  • 48.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    The role of lipid composition for insertion and stabilization of amino acids in membranes.2009Inngår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 130, nr 18, s. 185101-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    While most membrane protein helices are clearly hydrophobic, recent experiments have indicated that it is possible to insert marginally hydrophobic helices into bilayers and have suggested apparent in vivo free energies of insertion for charged residues that are low, e.g., a few kcals for arginine. In contrast, a number of biophysical simulation studies have predicted that the bilayer interior is close to a pure hydrophobic environment with large penalties for hydrophilic amino acids--and yet the experimental scales do significantly better at predicting actual membrane proteins from sequence. Here, we have systematically studied the dependence of the free energy profiles on lipid properties, including tail length, saturation, headgroup hydrogen bond strength, and charge, both to see to whether the in vivo insertion can be explained in whole or part from lipid composition of the endoplasmic reticulum (ER) membranes, and if the solvation properties can help interpret how protein function depends on the lipids. We find that lipid charge is important to stabilize charged amino acids inside the bilayer (with implications, e.g., for ion channels), that thicker bilayers have higher solvation costs for hydrophilic side chains, and that headgroup hydrogen bond strength determines how adaptive the lipids are as a hydrophobic/hydrophilic solvent. None of the different free energy profiles are even close to the low apparent in vivo insertion cost, which suggests that regardless of the specific ER membrane composition the current experimental results cannot be explained by normal lipid-type variation.

  • 49.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Titratable amino acid solvation in lipid membranes as a function of protonation state.2009Inngår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, nr 1, s. 245-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Knowledge about the insertion and stabilization of membrane proteins is a key step toward understanding their function and enabling membrane protein design. Transmembrane helices are normally quite hydrophobic so as to efficiently insert into membranes, but there are many exceptions with polar or titratable residues. An obvious example is the S4 helices of voltage-gated ion channels with up to 4 arginines, leading to vivid discussion about whether such helices can insert spontaneously, and if so, what their conformation, protonation state, and cost of insertion really are. To address this question, we have determined geometric and energetic solvation properties for different protonation states of the titrateable amino acids, including hydration, side chain orientation, free energy profiles, and effects on the membrane thickness. As expected, charged states are significantly more expensive to insert (8-16 kcal/mol) than neutral variants (1-3 kcal/mol). Although both sets of values exhibit quite high relative correlation with experimental in vivo hydrophobicity scales, the magnitudes of the in vivo hydrophobicity scales are much lower and strikingly appears as a compressed version of the calculated values. This agrees well with computational studies on longer lipids but results in an obvious paradox: the differences between in vivo insertion and simulations cannot be explained by methodological differences in force fields, possible limited hydrophobic thickness of the endoplasmic reticulum (ER) membrane, or parameters; even anionic lipid head groups (PG) only have limited effect on charged side chains, and virtually none for hydrophobic ones. This leads us to propose a model for in vivo insertion that could reconcile these differences and explain the correlation: if there are considerable hydrophobic barriers inside the translocon, the experimental reference state for the solvation free energy when comparing insertion/translocation in vivo would be quite close to the bilayer environment rather than water.

  • 50.
    Kasimova, Marina A.
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.
    Lindahl, Erik
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.
    Delemotte, L.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Determining the molecular basis of voltage sensitivity in membrane proteins2018Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 215, nr 10, s. 1444-1458Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested. 

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