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  • 1.
    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.

  • 2.
    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.

  • 3. Elber, R.
    et al.
    Ruymgaart, A. P.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    SHAKE parallelization2011In: The European Physical Journal Special Topics, ISSN 1951-6355, E-ISSN 1951-6401, Vol. 200, no 1, p. 211-223Article, review/survey (Refereed)
    Abstract [en]

    SHAKE is a widely used algorithm to impose general holonomic constraints during molecular simulations. By imposing constraints on stiff degrees of freedom that require integration with small time steps (without the constraints) we are able to calculate trajectories with time steps larger by approximately a factor of two. The larger time step makes it possible to run longer simulations. Another approach to extend the scope of Molecular Dynamics is parallelization. Parallelization speeds up the calculation of the forces between the atoms and makes it possible to compute longer trajectories with better statistics for thermodynamic and kinetic averages. A combination of SHAKE and parallelism is therefore highly desired. Unfortunately, the most widely used SHAKE algorithm (of bond relaxation) is inappropriate for parallelization and alternatives are needed. The alternatives must minimize communication, lead to good load balancing, and offer significantly better performance than the bond relaxation approach. The algorithm should also scale with the number of processors. We describe the theory behind different implementations of constrained dynamics on parallel systems, and their implementation on common architectures.

  • 4.
    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)
  • 5. Engin, Ozge
    et al.
    Villa, Alessandra
    Sayar, Mehmet
    Hess, Berk
    Driving forces for adsorption of amphiphilic peptides to the air-water interface.2010In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, no 34, p. 11093-11101Article in journal (Refereed)
    Abstract [en]

    We have studied the partitioning of amphiphilic peptides at the air-water interface. The free energy of adsorption from bulk to interface was calculated by determining the potential of mean force via atomistic molecular dynamics simulations. To this end a method is introduced to restrain or constrain the center of mass of a group of molecules in a periodic system. The model amphiphilic peptides are composed of alternating valine and asparagine residues. The decomposition of the free energy difference between the bulk and interface is studied for different peptide block lengths. Our analysis revealed that for short amphiphilic peptides the surface driving force dominantly stems from the dehydration of hydrophobic side chains. The only opposing force is associated with the loss of orientational freedom of the peptide at the interface. For the peptides studied, the free energy difference scales linearly with the size of the molecule, since the peptides mainly adopt extended conformations both in bulk and at the interface. The free energy difference depends strongly on the water model, which can be rationalized through the hydration thermodynamics of hydrophobic solutes. Finally, we measured the reduction of the surface tension associated with complete coverage of the interface with peptides.

  • 6. Ganguly, Pritam
    et al.
    Schravendijk, Pim
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. Technische Universität Darmstadt, Germany; Stockholm University, Sweden .
    van der Vegt, Nico F. A.
    Ion Pairing in Aqueous Electrolyte Solutions with Biologically Relevant Anions2011In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, no 13, p. 3734-3739Article in journal (Refereed)
    Abstract [en]

    We performed molecular simulations to study ion pairing in aqueous solutions. Our results indicate that ion specific interactions of Li+, Na+, and K+ with the dimethyl phosphate anion are solvent-mediated. The same mechanism applies to carboxylate ions, as has been illustrated in earlier simulations of aqueous alkali acetate solutions. Contact ion pairs play only a minor role or no role at all in determining the solution structure and ion specific thermodynamics of these systems. On the basis of the Kirkwood Buff theory of solution we furthermore show that the well-known reversal of the Hofmeister series of salt activity coefficients, comparing chloride or bromide with dimethyl phosphate or acetate, is caused by changing from a contact pairing mechanism in the former system to a solvent-mediated interaction mechanism in the latter system.

  • 7.
    Ghiringhelli, Luca M
    et al.
    Max-Planck-Institute for Polymer Research, Mainz, Germany.
    Hess, Berk
    Max-Planck-Institute for Polymer Research, Mainz, Germany.
    van der Vegt, Nico F A
    Max-Planck-Institute for Polymer Research, Mainz, Germany.
    Delle Site, Luigi
    Max-Planck-Institute for Polymer Research, Mainz, Germany.
    Competing adsorption between hydrated peptides and water onto metal surfaces: from electronic to conformational properties2008In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 130, no 40, p. 13460-13464Article in journal (Refereed)
    Abstract [en]

    Inorganic-(bio)organic interfaces are of central importance in many fields of current research. Theoretical and computational tools face the difficult problem of the different time and length scales that are involved and linked in a nontrivial way. In this work, a recently proposed hierarchical quantum-classical scale-bridging approach is further developed to study large flexible molecules. The approach is then applied to study the adsorption of oligopeptides on a hydrophilic Pt(111) surface under complete wetting conditions. We examine histidine sequences, which are well known for their binding affinity to metal surfaces. Based on a comparison with phenylalanine, which binds as strong as histidine under high vacuum conditions but, as we show, has no surface affinity under wet conditions, we illustrate the mediating effects of near-surface water molecules. These contribute significantly to the mechanism and strength of peptide binding. In addition to providing physical-chemical insights in the mechanism of surface binding, our computational approach provides future opportunities for surface-specific sequence design.

  • 8. Groenhof, Gerrit
    et al.
    Bouxin-Cademartory, Mathieu
    Hess, Berk
    De Visser, Sam P
    Berendsen, Herman J C
    Olivucci, Massimo
    Mark, Alan E
    Robb, Michael A
    Photoactivation of the photoactive yellow protein: why photon absorption triggers a trans-to-cis Isomerization of the chromophore in the protein.2004In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 13, p. 4228-4233Article in journal (Refereed)
    Abstract [en]

    Atomistic QM/MM simulations have been carried out on the complete photocycle of Photoactive Yellow Protein, a bacterial photoreceptor, in which blue light triggers isomerization of a covalently bound chromophore. The "chemical role" of the protein cavity in the control of the photoisomerization step has been elucidated. Isomerization is facilitated due to preferential electrostatic stabilization of the chromophore's excited state by the guanidium group of Arg52, located just above the negatively charged chromophore ring. In vacuo isomerization does not occur. Isomerization of the double bond is enhanced relative to isomerization of a single bond due to the steric interactions between the phenyl ring of the chromophore and the side chains of Arg52 and Phe62. In the isomerized configuration (ground-state cis), a proton transfer from Glu46 to the chromophore is far more probable than in the initial configuration (ground-state trans). It is this proton transfer that initiates the conformational changes within the protein, which are believed to lead to signaling.

  • 9. Hess, Berk
    et al.
    Harings, Jules A W
    Rastogi, Sanjay
    Vegt, Nico F A van der
    Interaction of water with N,N'-1,2-ethanediyl-bis(6-hydroxy-hexanamide) crystals: a simulation study2009In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 3, p. 627-31Article in journal (Refereed)
    Abstract [en]

    Recently it has been shown, using a variety of experimental techniques, that water can be hosted in N,N'-1,2-ethanediyl-bis(6-hydroxy-hexanamide) crystals. It forms stable interactions with the hydroxyl groups at the ends of the molecule, as well as with the amide groups. However, with experimental techniques one can not observe the exact hydrogen bonding geometries of the physically bound water molecules. Here a series of molecular dynamics simulations is presented that provide an atomistically detailed picture of the interactions of water with different parts of the crystals.

  • 10. Hess, Berk
    et al.
    Holm, Christian
    van der Vegt, Nico
    Modeling multibody effects in ionic solutions with a concentration dependent dielectric permittivity2006In: Physical Review Letters, ISSN 0031-9007, E-ISSN 1079-7114, Vol. 96, no 14, p. 147801-Article in journal (Refereed)
    Abstract [en]

    We report a new strategy to parametrize effective ion-ion potentials for implicit solvent simulations of charged systems. The effective potential includes a pair term and a Coulomb term that by means of a concentration dependent dielectric permittivity takes into account multibody effects. We demonstrate that this approach allows us to accurately reproduce the solution osmotic properties and the ion coordination up to concentrations of 2.8 M aqueous NaCl.

  • 11. Hess, Berk
    et al.
    Holm, Christian
    van der Vegt, Nico
    Osmotic coefficients of atomistic NaCl (aq) force fields2006In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 124, no 16, p. 164509-Article in journal (Refereed)
    Abstract [en]

    Solvated ions are becoming increasingly important for (bio)molecular simulations. But there are not much suitable data to validate the intermediate-range solution structure that ion-water force fields produce. We compare six selected combinations of four biomolecular Na-Cl force fields and four popular water models by means of effective ion-ion potentials. First we derive an effective potential at high dilution from simulations of two ions in explicit water. At higher ionic concentration multibody effects will become important. We propose to capture those by employing a concentration dependent dielectric permittivity. With the so obtained effective potentials we then perform implicit solvent simulations. We demonstrate that our effective potentials accurately reproduce ion-ion coordination numbers and the local structure. They allow us furthermore to calculate osmotic coefficients that can be directly compared with experimental data. We show that the osmotic coefficient is a sensitive and accurate measure for the effective ion-ion interactions and the intermediate-range structure of the solution. It is therefore a suitable and useful quantity for validating and parametrizing atomistic ion-water force fields.

  • 12.
    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.

  • 13. Hess, Berk
    et al.
    van der Vegt, Nico F A
    Cation specific binding with protein surface charges2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 32, p. 13296-300Article in journal (Refereed)
    Abstract [en]

    Biological organization depends on a sensitive balance of noncovalent interactions, in particular also those involving interactions between ions. Ion-pairing is qualitatively described by the law of "matching water affinities." This law predicts that cations and anions (with equal valence) form stable contact ion pairs if their sizes match. We show that this simple physical model fails to describe the interaction of cations with (molecular) anions of weak carboxylic acids, which are present on the surfaces of many intra- and extracellular proteins. We performed molecular simulations with quantitatively accurate models and observed that the order K(+) < Na(+) < Li(+) of increasing binding affinity with carboxylate ions is caused by a stronger preference for forming weak solvent-shared ion pairs. The relative insignificance of contact pair interactions with protein surfaces indicates that thermodynamic stability and interactions between proteins in alkali salt solutions is governed by interactions mediated through hydration water molecules.

  • 14. Hess, Berk
    et al.
    van der Vegt, Nico F A
    Hydration thermodynamic properties of amino acid analogues: a systematic comparison of biomolecular force fields and water models2006In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 35, p. 17616-17626Article in journal (Refereed)
    Abstract [en]

    We present an extensive study on hydration thermodynamic properties of analogues of 13 amino acid side chains at 298 K and 1 atm. The hydration free energies DeltaG, entropies DeltaS, enthalpies DeltaH, and heat capacities Deltac(P)() were determined for 10 combinations of force fields and water models. The statistical sampling was extended such that precisions of 0.3, 0.8, 0.8 kJ/mol and 25 J/(mol K) were reached for DeltaG, TDeltaS, DeltaH, and Deltac(P)(), respectively. The three force fields used in this study are AMBER99, GROMOS 53A6, and OPLS-AA; the five water models are SPC, SPC/E, TIP3P, TIP4P, and TIP4P-Ew. We found that the choice of water model strongly influences the accuracy of the calculated hydration entropies, enthalpies, and heat capacities, while differences in accuracy between the force fields are small. On the basis of an analysis of the hydrophobic analogues of the amino acid side chains, we discuss what properties of the water models are responsible for the observed discrepancies between computed and experimental values. The SPC/E water model performs best with all three biomolecular force fields.

  • 15.
    Hess, Berk
    et al.
    Max-Planck Institute for Polymer Research, Ackermannweg 10.
    van der Vegt, Nico F A
    Solvent-averaged potentials for alkali-, earth alkali-, and alkylammonium halide aqueous solutions2007In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 127, no 23, p. 234508-Article in journal (Refereed)
    Abstract [en]

    We derive effective, solvent-free ion-ion potentials for alkali-, earth alkali-, and alkylammonium halide aqueous solutions. The implicit solvent potentials are parametrized to reproduce experimental osmotic coefficients. The modeling approach minimizes the amount of input required from atomistic (force field) models, which usually predict large variations in the effective ion-ion potentials at short distances. For the smaller ion species, the reported potentials are composed of a Coulomb and a Weeks-Chandler-Andersen term. For larger ions, we find that an additional, attractive potential is required at the contact minimum, which is related to solvent degrees of freedom that are usually not accounted for in standard electrostatics models. The reported potentials provide a simple and accurate force field for use in molecular dynamics and Monte Carlo simulations of (poly-)electrolyte systems.

  • 16.
    Johansson, Petter
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Carlson, Andreas
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Water-substrate physico-chemistry in wetting dynamics2015In: Journal of Fluid Mechanics, ISSN 0022-1120, E-ISSN 1469-7645, Vol. 781, p. 695-711Article in journal (Refereed)
    Abstract [en]

    We consider the wetting of water droplets on substrates with different chemical composition and molecular spacing, but with an identical equilibrium contact angle. A combined approach of large-scale molecular dynamics simulations and a continuum phase field model allows us to identify and quantify the influence of the microscopic physics at the contact line on the macroscopic droplet dynamics. We show that the substrate physico-chemistry, in particular hydrogen bonding, can significantly alter the flow. Since the material parameters are systematically derived from the atomistic simulations, our continuum model has only one adjustable parameter, which appears as a friction factor at the contact line. The continuum model approaches the atomistic wetting rate only when we adjust this contact line friction factor. However, the flow appears to he qualitatively different when comparing the atomistic and continuum models, highlighting that non-trivial continuum effects can come into play near the interface of the wetting front.

  • 17.
    Johansson, Petter
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Hess, Berk
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Molecular origin of contact line friction in dynamic wetting2018In: Physical Review Fluids, E-ISSN 2469-990X, Vol. 3, no 7, article id 074201Article in journal (Refereed)
    Abstract [en]

    A hydrophilic liquid, such as water, forms hydrogen bonds with a hydrophilic substrate. The strength and locality of the hydrogen bonding interactions prohibit slip of the liquid over the substrate. The question then arises how the contact line can advance during wetting. Using large-scale molecular dynamics simulations we show that the contact line advances by single molecules moving ahead of the contact line through two distinct processes: either moving over or displacing other liquid molecules. In both processes friction occurs at the molecular scale. We measure the energy dissipation at the contact line and show that it is of the same magnitude as the dissipation in the bulk of a droplet. The friction increases significantly as the contact angle decreases, which suggests suggests thermal activation plays a role. We provide a simple model that is consistent with the observations.

  • 18. Kasson, Peter M.
    et al.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Probing microscopic material properties inside simulated membranes through spatially resolved three-dimensional local pressure fields and surface tensions2013In: Chemistry and Physics of Lipids, ISSN 0009-3084, E-ISSN 1873-2941, Vol. 169, p. 106-112Article in journal (Refereed)
    Abstract [en]

    Cellular lipid membranes are spatially inhomogeneous soft materials. Materials properties such as pressure and surface tension thus show important microscopic-scale variation that is critical to many biological functions. We present a means to calculate pressure and surface tension in a 3D-resolved manner within molecular-dynamics simulations and show how such measurements can yield important insight. We also present the first corrections to local virial and pressure fields to account for the constraints typically used in lipid simulations that otherwise cause problems in highly oriented systems such as bilayers. Based on simulations of an asymmetric bacterial ion channel in a POPC bilayer, we demonstrate how 3D-resolved pressure can probe for both short-range and long-range effects from the protein on the membrane environment. We also show how surface tension is a sensitive metric for inter-leaflet equilibrium and can be used to detect even subtle imbalances between bilayer leaflets in a membrane-protein simulation. Since surface tension is known to modulate the function of many proteins, this effect is an important consideration for predictions of ion channel function. We outline a strategy by which our local pressure measurements, which we make available within a version of the GROMACS simulation package, may be used to design optimally equilibrated membrane-protein simulations.

  • 19. Kutzner, C.
    et al.
    Apostolov, Rossen
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Grubmüller, H.
    Scaling of the GROMACS 4.6 molecular dynamics code on SuperMUC2014In: Advances in Parallel Computing, ISSN 0927-5452, E-ISSN 1879-808X, Vol. 25, p. 722-727Article in journal (Refereed)
    Abstract [en]

    Here we report on the performance of GROMACS 4.6 on the SuperMUC cluster at the Leibniz Rechenzentrum in Garching. We carried out benchmarks with three biomolecular systems consisting of eighty thousand to twelve million atoms in a strong scaling test each. The twelve million atom simulation system reached a performance of 49 nanoseconds per day on 32,768 cores.

  • 20.
    Larsson, Per
    et al.
    Stockholm Univ.
    Hess, Berk
    Stockholm Univ.
    Lindahl, Erik
    Stockholm Univ.
    Algorithm improvements for molecular dynamics simulations2011In: Wiley Interdisciplinary Reviews. Computational Molecular Science, ISSN 1759-0884, Vol. 1, no 1, p. 93-108Article in journal (Refereed)
    Abstract [en]

    High-performance implementations of molecular dynamics (MD) simulations play an important role in the study of macromolecules. Recent advances in both hardware and simulation software have extended the accessible time scales significantly, but the more complex algorithms used in many codes today occasionally make it difficult to understand the program flow and data structures without at least some knowledge about the underlying ideas used to improve performance. In this review, we discuss some of the currently most important areas of algorithm improvement to accelerate MD, including floating-point maths, techniques to accelerate nonbonded interactions, and methods to allow multiple or extended time steps. There is also a strong trend of increased parallelization on different levels, including both distributed memory domain decomposition, stream processing algorithms running, e. g., on graphics processing units hardware, and last but not least techniques to decouple simulations to enable massive parallelism on next-generation supercomputers or distributed computing. We describe some of the impacts these algorithms are having in current performance, and also how we believe they can be combined in the future.

  • 21.
    Lindahl, V.
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Physics.
    Lidmar, Jack
    KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Physics.
    Riemann metric approach to optimal sampling of multidimensional free-energy landscapes2018In: Physical review. E, ISSN 2470-0045, E-ISSN 2470-0053, Vol. 98, no 2, article id 023312Article in journal (Refereed)
    Abstract [en]

    Exploring the free-energy landscape along reaction coordinates or system parameters λ is central to many studies of high-dimensional model systems in physics, e.g., large molecules or spin glasses. In simulations this usually requires sampling conformational transitions or phase transitions, but efficient sampling is often difficult to attain due to the roughness of the energy landscape. For Boltzmann distributions, crossing rates decrease exponentially with free-energy barrier heights. Thus, exponential acceleration can be achieved in simulations by applying an artificial bias along λ tuned such that a flat target distribution is obtained. A flat distribution is, however, an ambiguous concept unless a proper metric is used and is generally suboptimal. Here we propose a multidimensional Riemann metric, which takes the local diffusion into account, and redefine uniform sampling such that it is invariant under nonlinear coordinate transformations. We use the metric in combination with the accelerated weight histogram method, a free-energy calculation and sampling method, to adaptively optimize sampling toward the target distribution prescribed by the metric. We demonstrate that for complex problems, such as molecular dynamics simulations of DNA base-pair opening, sampling uniformly according to the metric, which can be calculated without significant computational overhead, improves sampling efficiency by 50%-70%.

  • 22.
    Lindahl, Viveca
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Gourdon, Pontus
    Andersson, Magnus
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2995Article in journal (Refereed)
    Abstract [en]

    Aquaporin TIP2;1 is a protein channel permeable to both water and ammonia. The structural origin of ammonia selectivity remains obscure, but experiments have revealed that a double mutation renders it impermeable to ammonia without affecting water permeability. Here, we aim to reproduce and explain these observations by performing an extensive mutational study using microsecond long molecular dynamics simulations, applying the two popular force fields CHARMM36 and Amber ff99SB-ILDN. We calculate permeabilities and free energies along the channel axis for ammonia and water. For one force field, the permeability of the double mutant decreases by a factor of 2.5 for water and 4 for ammonia, increasing water selectivity by a factor of 1.6. We attribute this effect to decreased entropy of water in the pore, due to the observed increase in pore-water interactions and narrower pore. Additionally, we observe spontaneous opening and closing of the pore on the cytosolic side, which suggests a gating mechanism for the pore. Our results show that sampling methods and simulation times are sufficient to delineate even subtle effects of mutations on structure and function and to capture important long-timescale events, but also underline the importance of improving models further.

  • 23.
    Lindahl, Viveca
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lidmar, Jack
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Statistical Physics.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Accelerated weight histogram method for exploring free energy landscapes2014In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 141, no 4, p. 044110-Article in journal (Refereed)
    Abstract [en]

    Calculating free energies is an important and notoriously difficult task for molecular simulations. The rapid increase in computational power has made it possible to probe increasingly complex systems, yet extracting accurate free energies from these simulations remains a major challenge. Fully exploring the free energy landscape of, say, a biological macromolecule typically requires sampling large conformational changes and slow transitions. Often, the only feasible way to study such a system is to simulate it using an enhanced sampling method. The accelerated weight histogram (AWH) method is a new, efficient extended ensemble sampling technique which adaptively biases the simulation to promote exploration of the free energy landscape. The AWH method uses a probability weight histogram which allows for efficient free energy updates and results in an easy discretization procedure. A major advantage of the method is its general formulation, making it a powerful platform for developing further extensions and analyzing its relation to already existing methods. Here, we demonstrate its efficiency and general applicability by calculating the potential of mean force along a reaction coordinate for both a single dimension and multiple dimensions. We make use of a non-uniform, free energy dependent target distribution in reaction coordinate space so that computational efforts are not wasted on physically irrelevant regions. We present numerical results for molecular dynamics simulations of lithium acetate in solution and chignolin, a 10-residue long peptide that folds into a beta-hairpin. We further present practical guidelines for setting up and running an AWH simulation.

  • 24.
    Lindahl, Viveca
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lidmar, Jack
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Sampling rare biomolecular events with adaptive pulling simulations2015In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 44, p. S144-S144Article in journal (Other academic)
  • 25.
    Pronk, Sander
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Larsson, Per
    Stockholm University.
    Pouya, Iman
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Bowman, Gregory
    Haque, Imran
    Beauchamp, Kyle
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Pande, Vijay
    Kasson, Peter
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Copernicus: A new paradigm for parallel adaptive molecular dynamics2011In: Proceedings of 2011 SC - International Conference for High Performance Computing, Networking, Storage and Analysis, 2011, p. 60-Conference paper (Refereed)
    Abstract [en]

    Biomolecular simulation is a core application on supercomputers, but it is exceptionally difficult to achieve the strong scaling necessary to reach biologically relevant timescales. Here, we present a new paradigm for parallel adaptive molecular dynamics and a publicly available implementation: Copernicus. This framework combines performance-leading molecular dynamics parallelized on three levels (SIMD, threads, and message-passing) with kinetic clustering, statistical model building and real-time result monitoring. Copernicus enables execution as single parallel jobs with automatic resource allocation. Even for a small protein such as villin (9,864 atoms), Copernicus exhibits near-linear strong scaling from 1 to 5,376 AMD cores. Starting from extended chains we observe structures 0.6 Å from the native state within 30h, and achieve sufficient sampling to predict the native state without a priori knowledge after 80-90h. To match Copernicus'efficiency, a classical simulation would have to exceed 50 microseconds per day, currently infeasible even with custom hardware designed for simulations.

  • 26.
    Pronk, Sander
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pall, Szilard
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schulz, Roland
    Larsson, Per
    Bjelkmar, Pär
    Apostolov, Rossen
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Shirts, Michael R.
    Smith, Jeremy C.
    Kasson, Peter M.
    van der Spoel, David
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit2013In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 29, no 7, p. 845-854Article in journal (Refereed)
    Abstract [en]

    Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources. Results: Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations.

  • 27.
    Páll, Szilard
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    A flexible algorithm for calculating pair interactions on SIMD architectures2013In: Computer Physics Communications, ISSN 0010-4655, E-ISSN 1879-2944, Vol. 184, no 12, p. 2641-2650Article in journal (Refereed)
    Abstract [en]

    Calculating interactions or correlations between pairs of particles is typically the most time-consuming task in particle simulation or correlation analysis. Straightforward implementations using a double loop over particle pairs have traditionally worked well, especially since compilers usually do a good job of unrolling the inner loop. In order to reach high performance on modern CPU and accelerator architectures, single-instruction multiple-data (SIMD) parallelization has become essential. Avoiding memory bottlenecks is also increasingly important and requires reducing the ratio of memory to arithmetic operations. Moreover, when pairs only interact within a certain cut-off distance, good SIMD utilization can only be achieved by reordering input and output data, which quickly becomes a limiting factor. Here we present an algorithm for SIMD parallelization based on grouping a fixed number of particles, e.g. 2, 4, or 8, into spatial clusters. Calculating all interactions between particles in a pair of such clusters improves data reuse compared to the traditional scheme and results in a more efficient SIMD parallelization. Adjusting the cluster size allows the algorithm to map to SIMD units of various widths. This flexibility not only enables fast and efficient implementation on current CPUs and accelerator architectures like GPUs or Intel MIC, but it also makes the algorithm future-proof. We present the algorithm with an application to molecular dynamics simulations, where we can also make use of the effective buffering the method introduces.

  • 28.
    Páll, Szilárd
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Poster - 3D Tixels: A highly efficient algorithm for GPU/CPU-acceleration of molecular dynamics on heterogeneous parallel architectures2011In: SC - Proc. High Perform. Comput. Networking, Storage Anal. Companion, Co-located SC, 2011, p. 71-72Conference paper (Refereed)
    Abstract [en]

    Several GPU-based algorithms have been developed to ac-celerate biomolecular simulations, but although they pro-vide benefits over single-core implementations, they have not been able to surpass the performance of state-of-the art SIMD CPU implementations (e.g. GROMACS), not to mention efficient scaling. Here, we present a heteroge-nous parallelization that utilizes both CPU and GPU re-sources efficiently. A novel fixed-particle-number sub-cell algorithm for non-bonded force calculation was developed. The algorithm uses the SIMD width as algorithmic work unit, it is intrinsically future-proof since it can be adapted to future hardware. The CUDA non-bonded kernel imple-mentation achieves up to 60% work-efficiency, 1.5 IPC, and 95% L1 cache utilization. On the CPU OpenMP-parallelized SSE-accelerated code runs overlapping with GPU execution. Fully automated dynamic inter-process as well as CPU-GPU load balancing is employed. We achieve threefold speedup compared to equivalent GROMACS CPU code and show good strong and weak scaling. To the best of our knowledge this the fastest GPU molecular dynamics implementation presented to date.

  • 29.
    Saffar Shamshirgar, Davood
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Numerical Analysis, NA.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tornberg, Anna-Karin
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Numerical Analysis, NA.
    A comparison of the Spectral Ewald and Smooth Particle Mesh Ewald methods in GROMACSManuscript (preprint) (Other academic)
    Abstract [en]

    The smooth particle mesh Ewald (SPME) method is an FFT based methodfor the fast evaluation of electrostatic interactions under periodic boundaryconditions. A highly optimized implementation of this method is availablein GROMACS, a widely used software for molecular dynamics simulations.In this article, we compare a more recent method from the same family ofmethods, the spectral Ewald (SE) method, to the SPME method in termsof performance and efficiency. We consider serial and parallel implementa-tions of both methods for single and multiple core computations on a desktopmachine as well as the Beskow supercomputer at KTH Royal Institute ofTechnology. The implementation of the SE method has been well optimized,however not yet comparable to the level of the SPME implementation thathas been improved upon for many years. We show that the SE method isvery efficient whenever used to achieve high accuracy and that it already atthis level of optimization can be competitive for low accuracy demands.

  • 30.
    Saffar Shamshirgar, Davood
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Numerical Analysis, NA.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yokota, Rio
    Tornberg, Anna-Karin
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Numerical Analysis, NA.
    Regularized FMM for MD simulationsManuscript (preprint) (Other academic)
    Abstract [en]

    A regularized fast multipole method (FMM) which approximately conserves the total energy in Molecular dynamics (MD) simulations is presented. The new algorithm introduces a regularization which eliminates the discontinuity inherent in the FMM. This allows us to use FMM in simulations as a substitute for widely used FFT based methods. For a system of N particles, the computational complexity of the resulting method is still of order N though with a larger constant compared to the plain FMM. Numerical examples are provided to confirm that the new algorithm improves the accuracy and approximately conserves the long term total energy.

  • 31. Saint-Martin, Humberto
    et al.
    Hess, Berk
    Department of Applied Physics, Rijksuniversiteit Groningen.
    Berendsen, Herman J. C.
    An application of flexible constraints in Monte Carlo simulations of the isobaric-isothermal ensemble of liquid water and ice Ih with the polarizable and flexible mobile charge densities in harmonic oscillators model2004In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 120, no 23, p. 11133-11143Article in journal (Refereed)
    Abstract [en]

    The method of flexible constraints was implemented in a Monte Carlo code to perform numerical simulations of liquid water and ice Ih in the constant number of molecules, volume, and temperature and constant pressure, instead of volume ensembles, using the polarizable and flexible mobile charge densities in harmonic oscillators (MCDHO) model. The structural and energetic results for the liquid at T=298 K and rho=997 kg m(-3) were in good agreement with those obtained from molecular dynamics. The density obtained at P=1 atm with flexible constraints, rho=1008 kg m(-3), was slightly lower than with the classical sampling of the intramolecular vibrations, rho=1010 kg m(-3). The comparison of the structures and energies found for water hexamers and for ice Ih with six standard empirical models to those obtained with MCDHO, show this latter to perform better in describing water far from ambient conditions: the MCDHO minimum lattice energy, density, and lattice constants were in good agreement with experiment. The average angle HOH of the water molecule in ice was predicted to be slightly larger than in the liquid, yet 1.2% smaller than the experimental value.

  • 32.
    Schwaiger, Christine S.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Bjelkmar, Pär
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 6, p. 1446-1454Article in journal (Refereed)
    Abstract [en]

    The activation of voltage-gated ion channels is controlled by the S4 helix, with arginines every third residue. The x-ray structures are believed to reflect an open-inactivated state, and models propose combinations of translation, rotation, and tilt to reach the resting state. Recently, experiments and simulations have independently observed occurrence of 3(10)-helix in S4. This suggests S4 might make a transition from alpha- to 3(10)-helix in the gating process. Here, we show 3(10)-helix structure between 01 and R3 in the S4 segment of a voltage sensor appears to facilitate the early stage of the motion toward a down state. We use multiple microsecond-steered molecular simulations to calculate the work required for translating S4 both as a-helix and transformed to 3(10)-helix. The barrier appears to be caused by salt-bridge reformation simultaneous to R4 passing the F233 hydrophobic lock, and it is almost a factor-two lower with 3(10)-helix. The latter facilitates translation because R2/R3 line up to face E183/E226, which reduces the requirement to rotate S4. This is also reflected in a lower root mean-square deviation distortion of the rest of the voltage sensor. This supports the 3(10) hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.

  • 33.
    Schwaiger, Christine S.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Börjesson, Sara I.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Elinder, Fredrik
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Phe233 in the Voltage-Sensor is Rate Limiting for Channel Closure but not for the Opening2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 13A-13AArticle in journal (Other academic)
  • 34.
    Schwaiger, Christine S.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Cell Biology, Linköping, Sweden.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Wallner, Björn
    The voltage sensor deactivation barrier is altered by substitutions in the hydrophobic coreManuscript (preprint) (Other academic)
    Abstract [en]

    The gating of voltage-gated ion channels is caused by the arginine-rich S4 helix of the voltage sensor moving in response to an external potential. Exactly how this is accomplished is not yet fully known, but several studies now indicate S4 transiently adopts 310-conformation to facilitate the process. Here, we combine modeling of intermediate states based on experimental constraints with systematic in silico mutagenesis and free energy calculations to identify metastable states and characterize the energetics when moving between them. We show that states very close to the X-ray structure can be obtained with steered simulations starting from the intermediate state, and that several residues in the narrow hydrophobic band in the middle of the voltage sensor contribute to the free energy between the activated and intermediate states. The single most important is the structural barrier caused by the aromatic ring of F233. Substitution for smaller amino acids reduces the translation cost signi cantly, while introduction of a larger ring increases it, both con rming experimental activation shift results. In fact, the rigid ring appears to determine the barrier for the voltage sensor gating process, with a close interaction between the ring rotation and the arginine barrier crossing.

     

  • 35.
    Schwaiger, Christine S.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Börjesson, Sara I.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wallner, Björn
    Elinder, Fredrik
    Linköping University, Linköping, Sweden.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    The free energy barrier for arginine gating charge translation is altered by mutations in the voltage sensor domain.2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e45880-Article in journal (Refereed)
    Abstract [en]

    The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C), modeled from experimental constraints. We show that conformations within 3 Å of the X-ray structure are obtained in simulations starting from the C model, and directly observe the previously suggested sliding 3-helix region in S4. Through systematic free energy calculations, we show that the C state is a stable intermediate conformation and determine free energy profiles for moving between the states without constraints. Mutations indicate several residues in a narrow hydrophobic band in the voltage sensor contribute to the barrier between the open and C states, with F233 in the S2 helix having the largest influence. Substitution for smaller amino acids reduces the transition cost, while introduction of a larger ring increases it, largely confirming experimental activation shift results. There is a systematic correlation between the local aromatic ring rotation, the arginine barrier crossing, and the corresponding relative free energy. In particular, it appears to be more advantageous for the F233 side chain to rotate towards the extracellular side when arginines cross the hydrophobic region.

  • 36. Seibert, M. Marvin
    et al.
    Patriksson, Alexandra
    Hess, Berk
    Max Planck Institute for Polymer Research.
    van der Spoel, David
    Reproducible polypeptide folding and structure prediction using molecular dynamics simulations2005In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 354, no 1, p. 173-183Article in journal (Refereed)
    Abstract [en]

    The folding of a polypeptide from an extended state to a well-defined conformation is studied using microsecond classical molecular dynamics (MD) simulations and replica exchange molecular dynamics (REMD) simulations in explicit solvent and in vacuo. It is shown that the solvated peptide folds many times in the REMD simulations but only a few times in the conventional simulations. From the folding events in the classical simulations we estimate an approximate folding time of 1-2 micros. The REMD simulations allow enough sampling to deduce a detailed Gibbs free energy landscape in three dimensions. The global minimum of the energy landscape corresponds to the native state of the peptide as determined previously by nuclear magnetic resonance (NMR) experiments. Starting from an extended state it takes about 50 ns before the native structure appears in the REMD simulations, about an order of magnitude faster than conventional MD. The calculated melting curve is in good qualitative agreement with experiment. In vacuo, the peptide collapses rapidly to a conformation that is substantially different from the native state in solvent.

  • 37. Stueber, Dirk
    et al.
    Yu, Tsyr-Yan
    Hess, Berk
    Max-Planck-Institut für Polymerforschung, Germany.
    Kremer, Kurt
    O'Connor, Robert D
    Schaefer, Jacob
    Chain packing in polycarbonate glasses2010In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 132, no 10Article in journal (Refereed)
    Abstract [en]

    Chain packing in homogeneous blends of carbonate (13)C-labeled bisphenol A polycarbonate with either (i) CF(3)-labeled bisphenol A polycarbonate or (ii) ring-F-labeled bisphenol A polycarbonate has been characterized using (13)C{(19)F} rotational-echo double-resonance (REDOR) nuclear magnetic resonance. In both blends, the (13)C observed spin was at high concentration, and the (19)F dephasing or probe spin was at low concentration. In this situation, an analysis in terms of a distribution of isolated heteronuclear pairs of spins is valid. Nearest-neighbor separation of (13)C and (19)F labels was determined by accurately mapping the initial dipolar evolution using a shifted-pulse version of REDOR. Based on the results of this experiment, the average distance from a ring-fluorine to the nearest (13)C=O is more than 1.2 A greater than the corresponding CF(3)-(13)C=O distance. Next-nearest and more-distant-neighbor separations of labels were measured in a 416-rotor-cycle constant-time version of REDOR for both blends. Statistically significant local order was established for the nearest-neighbor labels in the methyl-labeled blend. These interchain packing results are in qualitative agreement with predictions based on coarse-grained simulations of a specially adapted model for bisphenol A polycarbonate. The model itself has been previously used to determine static and dynamic properties of polycarbonate with results in good agreement with those from rheological and neutron scattering experiments.

  • 38.
    Ullmann, R. T.
    et al.
    MPI Biophys, Theoret & Computat Biophys, Gottingen, Germany..
    Kutzner, C.
    MPI Biophys, Theoret & Computat Biophys, Gottingen, Germany..
    Beckmann, A.
    Julich Supercomp Ctr, IAS, Div Math, Julich, Germany..
    Kohnke, B.
    MPI Biophys, Theoret & Computat Biophys, Gottingen, Germany..
    Kabadashow, I.
    Julich Supercomp Ctr, IAS, Div Math, Julich, Germany..
    Dachsel, H.
    Julich Supercomp Ctr, IAS, Div Math, Julich, Germany..
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Grubmueller, H.
    MPI Biophys, Theoret & Computat Biophys, Gottingen, Germany..
    GromEx: Electrostatics with chemical variability for realistic molecular simulations on the exascale2015In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 44, p. S145-S145Article in journal (Other academic)
  • 39. van der Spoel, David
    et al.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    GROMACS-the road ahead2011In: WIRES COMPUT MOL SCI, ISSN 1759-0876, Vol. 1, no 5, p. 710-715Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics (MD) simulations form a powerful tool that is complementary to experiments and theory. They allow detailed investigations of both biological and chemical systems at the atomic level at timescales ranging from femtoseconds to milliseconds. Mechanisms and processes not accessible to experimental techniques can be followed in 'real time', and hypotheses based on experiments or theoretical arguments can be tested. Limits on the accuracy of results are mainly due to the physical models, the ratio of the complexity of the problem and the amount of computer time. Here, we review the state of the art in MD simulations with a focus on imminent challenges for the GROMACS (GROningen MAchine for Chemical Simulation) software. New hardware puts new requirements on software, while the breadth of applications and the amount of physical models implemented are increasing rapidly, highlighting shortcomings in the architecture of the programs. We sketch a road map for a popular scientific software package and discuss some of the choices to be made.

  • 40.
    Van Der Spoel, David
    et al.
    Uppsala University.
    Lindahl, Erik
    Stockholm University.
    Hess, Berk
    Max-Planck Institut Mainz.
    Groenhof, Gerrit
    Max-Planck Institut Göttingen.
    Mark, Alan E.
    Groningen University.
    Berendsen, Herman J. C.
    Groningen University.
    GROMACS: fast, flexible, and free2005In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 26, no 16, p. 1701-1718Article in journal (Refereed)
    Abstract [en]

    This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

  • 41. Villa, Alessandra
    et al.
    Hess, Berk
    Max-Planck-Institute for Polymer Research, Mainz, Germany.
    Saint-Martin, Humberto
    Dynamics and structure of Ln(III)-aqua ions: a comparative molecular dynamics study using ab initio based flexible and polarizable model potentials2009In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 20, p. 7270-7281Article in journal (Refereed)
    Abstract [en]

    Aqueous solutions of a light (Nd3+), a middle (Gd3+), and a heavy (Yb3+) lanthanide ion were studied using ab initio based flexible and polarizable analytical potentials in classical molecular dynamics simulations to describe their thermodynamic, structural, and dynamic features. To avoid the spurious demise of O-H bonds, it was necessary to reparametrize an existing water model, which resulted in an improved description of pure water. The good agreement of the results from the simulations with the experimental hydration enthalpies, the Ln(III)-water radial distribution functions, and the water-exchange rates validated the potentials, though the r(Ln-Ow) distances were 6% longer than the experimentally determined values. A nona-coordinated state was found for Nd3+ in 95% of the simulation, with a tricapped trigonal prism (TCTP) geometry; the corresponding water-exchange mechanism was found to be of dissociative interchange (Id) character through a short-lived octa-coordinated transition state in a square antiprism (SQA) geometry. An octa-coordinated state in SQA geometry was found for Yb3+ in 99% of the simulation, and the observed exchange events exhibited characteristics of an interchange (I) mechanism. For Gd3+ an equilibrium was observed between 8-fold SQA and 9-fold TCTP coordinated states that was maintained by the frequent exchange of a water molecule from the first hydration shell with the bulk, thus producing significant deviations from the ideal geometries, and a fast exchange rate. Though strong water-water interactions prevented a full alignment of the dipoles to the ion's electric field, the screening was found large enough as to limit its range to 5 A; water molecules further apart from the ion were found to have the same dipole as the molecules in the bulk, and a random orientation. The interplay among the water-ion and the water-water interactions determined the different coordination numbers and the different dynamics of the water exchange in the first hydration shell for each ion.

  • 42.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Improved Accuracy and Performance of Lennard-Jones Lattice Summation in GromacsManuscript (preprint) (Other academic)
  • 43.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties2013In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 9, no 8, p. 3527-3537Article in journal (Refereed)
    Abstract [en]

    The accuracy of electrostatic interactions in molecular dynamics advanced tremendously with the introduction of particle-mesh Ewald (PME) summation almost 20 years ago. Lattice summation electrostatics is now the de facto standard for most types of biomolecular simulations, and in particular, for lipid bilayers, it has been a critical improvement due to the large charges typically present in zwitterionic lipid headgroups. In contrast, Lennard-Jones interactions have continued to be handled with increasingly longer cutoffs, partly because few alternatives have been available despite significant difficulties in tuning cutoffs and parameters to reproduce lipid properties. Here, we present a new Lennard-Jones PME implementation applied to lipid bilayers. We confirm that long-range contributions are well approximated by dispersion corrections in simple systems such as pentadecane (which makes parameters transferable), but for inhomogeneous and anisotropic systems such as lipid bilayers there are large effects on surface tension, resulting in up to 5.5% deviations in area per lipid and order parameters-far larger than many differences for which reparameterization has been attempted. We further propose an approximation for combination rules in reciprocal space that significantly reduces the computational cost of Lennard-Jones PME and makes accurate treatment of all nonbonded interactions competitive with simulations employing long cutoffs. These results could potentially have broad impact on important applications such as membrane proteins and free energy calculations.

  • 44.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Pall, Szilard
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Abraham, Mark James
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Direct-Space Corrections Enable Fast and Accurate Lorentz-Berthelot Combination Rule Lennard-Jones Lattice Summation2015In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 11, no 12, p. 5737-5746Article in journal (Refereed)
    Abstract [en]

    Long-range lattice summation techniques such as the particle-mesh Ewald (PME) algorithm for electrostatics have been revolutionary to the precision and accuracy of molecular simulations in general. Despite the performance penalty associated with lattice summation electrostatics, few biomolecular simulations today are performed without it. There are increasingly strong arguments for moving in the same direction for Lennard-Jones (LJ) interactions, and by using geometric approximations of the combination rules in reciprocal space, we have been able to make a very high-performance implementation available in GROMACS. Here, we present a new way to correct for these approximations to achieve exact treatment of Lorentz-Berthelot combination rules within the cutoff, and only a very small approximation error remains outside the cutoff (a part that would be completely ignored without LJ-PME). This not only improves accuracy by almost an order of magnitude but also achieves absolute biomolecular simulation performance that is an order of magnitude faster than any other available lattice summation technique for LJ interactions. The implementation includes both CPU and GPU acceleration, and its combination with improved scaling LJ-PME simulations now provides performance close to the truncated potential methods in GROMACS but with much higher accuracy.

1 - 44 of 44
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