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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.

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  • 2.
    Aho, Noora
    et al.
    Nanoscience Center and Department of Chemistry, University of Jyväskylä, 40014Jyväskylä, Finland.
    Buslaev, Pavel
    Nanoscience Center and Department of Chemistry, University of Jyväskylä, 40014Jyväskylä, Finland.
    Jansen, Anton
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bauer, Paul
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Groenhof, Gerrit
    Nanoscience Center and Department of Chemistry, University of Jyväskylä, 40014Jyväskylä, Finland.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Scalable Constant pH Molecular Dynamics in GROMACS2022In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 18, no 10, p. 6148-6160Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics (MD) computer simulations are used routinely to compute atomistic trajectories of complex systems. Systems are simulated in various ensembles, depending on the experimental conditions one aims to mimic. While constant energy, temperature, volume, and pressure are rather straightforward to model, pH, which is an equally important parameter in experiments, is more difficult to account for in simulations. Although a constant pH algorithm based on the λ-dynamics approach by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414–2423] was implemented in a fork of the GROMACS molecular dynamics program, uptake has been rather limited, presumably due to the poor scaling of that code with respect to the number of titratable sites. To overcome this limitation, we implemented an alternative scheme for interpolating the Hamiltonians of the protonation states that makes the constant pH molecular dynamics simulations almost as fast as a normal MD simulation with GROMACS. In addition, we implemented a simpler scheme, called multisite representation, for modeling side chains with multiple titratable sites, such as imidazole rings. This scheme, which is based on constraining the sum of the λ-coordinates, not only reduces the complexity associated with parametrizing the intramolecular interactions between the sites but also is easily extendable to other molecules with multiple titratable sites. With the combination of a more efficient interpolation scheme and multisite representation of titratable groups, we anticipate a rapid uptake of constant pH molecular dynamics simulations within the GROMACS user community.

  • 3.
    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.

  • 4.
    Buslaev, Pavel
    et al.
    Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland.;Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland..
    Aho, Noora
    Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland.;Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland..
    Jansen, Anton
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Bauer, Paul
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Groenhof, Gerrit
    Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland.;Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland..
    Best Practices in Constant pH MD Simulations: Accuracy and Sampling2022In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 18, no 10, p. 6148-6160Article in journal (Refereed)
    Abstract [en]

    Various approaches have been proposed to include the effect of pH in molecular dynamics (MD) simulations. Among these, the A-dynamics approach proposed by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys. 1996, 105, 2414-2423] can be performed with little computational overhead and hfor each typeence be used to routinely perform MD simulations at microsecond time scales, as shown in the accompanying paper [Aho, N. et al. J. Chem. Theory Comput. 2022, DOI: 10.1021 /acs.jctc.2c00516]. At such time scales, however, the accuracy of the molecular mechanics force field and the parametrization becomes critical. Here, we address these issues and provide the community with guidelines on how to set up and perform long time scale constant pH MD simulations. We found that barriers associated with the torsions of side chains in the CHARMM36m force field are too high for reaching convergence in constant pH MD simulations on microsecond time scales. To avoid the high computational cost of extending the sampling, we propose small modifications to the force field to selectively reduce the torsional barriers. We demonstrate that with such modifications we obtain converged distributions of both protonation and torsional degrees of freedom and hence consistent pK(a) estimates, while the sampling of the overall configurational space accessible to proteins is unaffected as compared to normal MD simulations. We also show that the results of constant pH MD depend on the accuracy of the correction potentials. While these potentials are typically obtained by fitting a low-order polynomial to calculated free energy profiles, we find that higher order fits are essential to provide accurate and consistent results. By resolving problems in accuracy and sampling, the work described in this and the accompanying paper paves the way to the widespread application of constant pH MD beyond pK(a) prediction.

  • 5. 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.

  • 6.
    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)
  • 7. 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.

  • 8. 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.

  • 9.
    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.

  • 10. 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.

  • 11.
    Hess, Berk
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Gong, Jing
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Pall, Szilard
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Schlatter, Philipp
    KTH, School of Engineering Sciences (SCI), Mechanics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Peplinski, Adam
    KTH, School of Engineering Sciences (SCI), Mechanics, Stability, Transition and Control.
    Highly Tuned Small Matrix Multiplications Applied to Spectral Element Code Nek50002016Conference paper (Refereed)
  • 12. 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.

  • 13. 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.

  • 14. 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.

  • 15.
    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.

  • 16. 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.

  • 17. 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.

  • 18.
    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.

  • 19.
    Jansen, Anton
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Aho, Noora
    Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland.;Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland..
    Groenhof, Gerrit
    Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland.;Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland..
    Buslaev, Pavel
    Univ Jyvaskyla, Nanosci Ctr, Jyvaskyla 40014, Finland.;Univ Jyvaskyla, Dept Chem, Jyvaskyla 40014, Finland..
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    phbuilder: A Tool for Efficiently Setting up Constant pH Molecular Dynamics Simulations in GROMACS2024In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 64, no 3, p. 567-574Article in journal (Refereed)
    Abstract [en]

    Constant pH molecular dynamics (MD) is a powerful technique that allows the protonation state of residues to change dynamically, thereby enabling the study of pH dependence in a manner that has not been possible before. Recently, a constant pH implementation was incorporated into the GROMACS MD package. Although this implementation provides good accuracy and performance, manual modification and the preparation of simulation input files are required, which can be complicated, tedious, and prone to errors. To simplify and automate the setup process, we present phbuilder, a tool that automatically prepares constant pH MD simulations for GROMACS by modifying the input structure and topology as well as generating the necessary parameter files. phbuilder can prepare constant pH simulations from both initial structures and existing simulation systems, and it also provides functionality for performing titrations and single-site parametrizations of new titratable group types. The tool is freely available at www.gitlab.com/gromacs-constantph. We anticipate that phbuilder will make constant pH simulations easier to set up, thereby making them more accessible to the GROMACS user community.

  • 20.
    Jansen, Anton
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Bauer, Paul
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Howard, Rebecca
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, PO Box 1031, SE-171 21 Solna, Sweden.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, PO Box 1031, SE-171 21 Solna, Sweden.
    Constant-pH Molecular Dynamics Simulations of Closed and Open States of a Proton-gated Ion ChannelManuscript (preprint) (Other academic)
    Abstract [en]

    Although traditional molecular dynamics simulations successfully capture a variety of di erent molecular interactions, the protonation states of titratable residues are kept static. A recent constant-pH molecular dynamics implementation in the GROMACS package allows pH e ects to be captured dynamically, and promises to provide both the accuracy and computational performance required for studying pH-mediated conformational dynamics in large, complex systems containing hundreds of titratable residues. Here, we demonstrate the applicability of this constant-pH implementation by simulating the proton-gated ion channel GLIC at resting and activating pH, starting from closed and open structures. Our simulations identify residues E26 and E35 as especially pH-sensitive and reveal state-dependent pKa shifts at multiple residues, as well as side chain and domain rearrangements in line with the early stages of gating. Our results are consistent with several previous experimental  ndings, demonstrating the applicability of constant-pH simulations to elucidate pH-mediated activation mechanisms in multidomain membrane proteins, likely extensible to other complex systems.

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  • 21.
    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.

  • 22.
    Johansson, Petter
    et al.
    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. KTH, School of Engineering Sciences (SCI).
    Electrowetting diminishes contact line friction in dynamic wettingManuscript (preprint) (Other academic)
    Abstract [en]

    We use large-scale molecular dynamics to study dynamics at the three-phase contact line in electrowetting of water and electrolytes on no-slip substrates. Under the applied electrostatic potential the line friction at the contact line is diminished. The effect is consistent for droplets of different sizes as well as for both pure water and electrolyte solution droplets. We analyze the electric field at the contact line to show how it assists ions and dipolar molecules to advance the contact line. Without an electric field, the interaction between a substrate and a liquid has a very short range, mostly affecting the bottom, immobilized layer of liquid molecules which leads to high friction since mobile molecules are not pulled towards the surface. In electrowetting, the electric field attractscharged and polar molecules over a longer range which diminishes the friction.

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    fulltext
  • 23.
    Johansson, Petter
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Electrowetting diminishes contact line friction in molecular wetting2020In: Physical Review Fluids, E-ISSN 2469-990X, Vol. 5, no 6, article id 064203Article in journal (Refereed)
    Abstract [en]

    We use large-scale molecular dynamics to study the dynamics at the three-phase contact line in electrowetting of water and electrolytes on no-slip substrates. Under the applied electrostatic potential the line friction at the contact line is diminished. The effect is consistent for droplets of different sizes as well as for both pure water and electrolyte solution droplets. We analyze the electric field at the contact line to show how it assists ions and dipolar molecules to advance the contact line. Without an electric field, the interaction between a substrate and a liquid has a very short range, mostly affecting the bottom, immobilized layer of liquid molecules which leads to high friction since mobile molecules are not pulled towards the surface. In electrowetting, the electric field attracts charged and polar molecules over a longer range, which diminishes the friction.

  • 24.
    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.

  • 25. 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.

  • 26. Kohnke, B
    et al.
    Ullmann, T R
    Beckmann, A
    Kabadshow, I
    Haensel, D
    Morgenstern, L
    Dobrev, P
    Groenhof, G
    Kutzner, C
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Dachsel, H
    Grubmüller, H
    Gromex: A scalable and versatile fast multipole method for biomolecular simulation2020In: Lecture Notes in Computational Science and Engineering: A scalable and versatile fast multipole method for biomolecular simulation, Springer , 2020, p. 517-543Chapter in book (Other academic)
    Abstract [en]

    Atomistic simulations of large biomolecular systems with chemical variability such as constant pH dynamic protonation offer multiple challenges in high performance computing. One of them is the correct treatment of the involved electrostatics in an efficient and highly scalable way. Here we review and assess two of the main building blocks that will permit such simulations: (1) An electrostatics library based on the Fast Multipole Method (FMM) that treats local alternative charge distributions with minimal overhead, and (2) A λ-dynamics module working in tandem with the FMM that enables various types of chemical transitions during the simulation. Our λ-dynamics and FMM implementations do not rely on third-party libraries but are exclusively using C++ language features and they are tailored to the specific requirements of molecular dynamics simulation suites such as GROMACS. The FMM library supports fractional tree depths and allows for rigorous error control and automatic performance optimization at runtime. Near-optimal performance is achieved on various SIMD architectures and on GPUs using CUDA. For exascale systems, we expect our approach to outperform current implementations based on Particle Mesh Ewald (PME) electrostatics, because FMM avoids the communication bottlenecks caused by the parallel fast Fourier transformations needed for PME. 

  • 27.
    Kohnke, Bartosz
    et al.
    Max Planck Inst Biophys Chem, Dept Theoret & Computat Biophys, Gottingen, Germany..
    Ullmann, R. Thomas
    Max Planck Inst Biophys Chem, Dept Theoret & Computat Biophys, Gottingen, Germany..
    Kutzner, Carsten
    Max Planck Inst Biophys Chem, Dept Theoret & Computat Biophys, Gottingen, Germany..
    Beckmann, Andreas
    Forschungszentrum Julich, IAS, Julich, Germany..
    Haensel, David
    Forschungszentrum Julich, IAS, Julich, Germany..
    Kabadshow, Ivo
    Forschungszentrum Julich, IAS, Julich, Germany..
    Dachsel, Holger
    Forschungszentrum Julich, IAS, Julich, Germany..
    Hess, Berk
    KTH, School of Engineering Sciences (SCI).
    Grubmueller, Helmut
    Max Planck Inst Biophys Chem, Dept Theoret & Computat Biophys, Gottingen, Germany..
    A Flexible, GPU - Powered Fast Multipole Method for Realistic Biomolecular Simulations in Gromacs2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 448A-448AArticle in journal (Other academic)
  • 28. 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.

  • 29.
    Lacis, Ugis
    et al.
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Johansson, Petter
    KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Fullana, Tomas
    Sorbonne Université.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI).
    Amberg, Gustav
    KTH, Superseded Departments (pre-2005), Mechanics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. Södertorn University, Stockholm, Sweden.
    Bagheri, Shervin
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Zaleski, Stephane
    Sorbonne Université.
    Steady moving contact line of water over a no-slip substrateManuscript (preprint) (Other academic)
    Abstract [en]

    The movement of the triple contact line plays a crucial role inmany applications such as ink-jet printing, liquid coating and drainage(imbibition) in porous media. To design accurate computational toolsfor these applications, predictive models of the moving contact line areneeded. However, the basic mechanisms responsible for movement ofthe triple contact line are not well understood but still debated. We investigatethe movement of the contact line between water, vapour anda silica-like solid surface under steady conditions in low capillary numberregime. We use molecular dynamics (MD) with an atomistic watermodel to simulate a nanoscopic drop between two moving plates. Weinclude hydrogen bonding between the water molecules and the solidsubstrate, which leads to a sub-molecular slip length. We benchmarktwo continuum methods, the Cahn{Hilliard phase-eld (PF) model anda volume-of-uid (VOF) model, against MD results.We show that bothcontinuum models reproduce the statistical measures obtained fromMD reasonably well, with a trade-o in accuracy. We demonstrate theimportance of the phase-eld mobility parameter and the local sliplength in accurately modelling the moving contact line.

  • 30.
    Lacis, Ugis
    et al.
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics.
    Johansson, Petter
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fullana, Tomas
    Sorbonne Univ, Paris, France.;CNRS, Paris, France..
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Amberg, Gustav
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics. Södertörn Univ, Stockholm, Sweden..
    Bagheri, Shervin
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics.
    Zaleski, Stephane
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. Sorbonne Univ, Paris, France.;CNRS, Paris, France..
    Steady moving contact line of water over a no-slip substrate Challenges in benchmarking phase-field and volume-of-fluid methods against molecular dynamics simulations2020In: The European Physical Journal Special Topics, ISSN 1951-6355, E-ISSN 1951-6401, Vol. 229, no 10, p. 1897-1921Article in journal (Refereed)
    Abstract [en]

    The movement of the triple contact line plays a crucial role in many applications such as ink-jet printing, liquid coating and drainage (imbibition) in porous media. To design accurate computational tools for these applications, predictive models of the moving contact line are needed. However, the basic mechanisms responsible for movement of the triple contact line are not well understood but still debated. We investigate the movement of the contact line between water, vapour and a silica-like solid surface under steady conditions in low capillary number regime. We use molecular dynamics (MD) with an atomistic water model to simulate a nanoscopic drop between two moving plates. We include hydrogen bonding between the water molecules and the solid substrate, which leads to a sub-molecular slip length. We benchmark two continuum methods, the Cahn-Hilliard phase-field (PF) model and a volume-of-fluid (VOF) model, against MD results. We show that both continuum models reproduce the statistical measures obtained from MD reasonably well, with a trade-off in accuracy. We demonstrate the importance of the phase-field mobility parameter and the local slip length in accurately modelling the moving contact line.

  • 31.
    Larsson, Per
    et al.
    Stockholm Univ.
    Hess, Berk
    Stockholm Univ.
    Lindahl, Erik
    Stockholm Univ.
    Algorithm improvements for molecular dynamics simulations2011In: WIREs Computational Molecular Science, ISSN 1759-0876, E-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.

  • 32.
    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%.

  • 33.
    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, 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.

  • 34.
    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.

  • 35.
    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)
  • 36.
    Lindahl, Viveca
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Villa, Alessandra
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sequence dependency of canonical base pair opening in the DNA double helix2017In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 4, article id e1005463Article in journal (Refereed)
    Abstract [en]

    The flipping-out of a DNA base from the double helical structure is a key step of many cellular processes, such as DNA replication, modification and repair. Base pair opening is the first step of base flipping and the exact mechanism is still not well understood. We investigate sequence effects on base pair opening using extensive classical molecular dynamics simulations targeting the opening of 11 different canonical base pairs in two DNA sequences. Two popular biomolecular force fields are applied. To enhance sampling and calculate free energies, we bias the simulation along a simple distance coordinate using a newly developed adaptive sampling algorithm. The simulation is guided back and forth along the coordinate, allowing for multiple opening pathways. We compare the calculated free energies with those from an NMR study and check assumptions of the model used for interpreting the NMR data. Our results further show that the neighboring sequence is an important factor for the opening free energy, but also indicates that other sequence effects may play a role. All base pairs are observed to have a propensity for opening toward the major groove. The preferred opening base is cytosine for GC base pairs, while for AT there is sequence dependent competition between the two bases. For AT opening, we identify two non-canonical base pair interactions contributing to a local minimum in the free energy profile. For both AT and CG we observe long-lived interactions with water and with sodium ions at specific sites on the open base pair.

  • 37.
    Lundborg, M.
    et al.
    ERCO Pharma AB, S-11439 Stockholm, Sweden..
    Lidmar, Jack
    KTH, School of Engineering Sciences (SCI), Physics, Condensed Matter Theory.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    The accelerated weight histogram method for alchemical free energy calculations2021In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 154, no 20, article id 204103Article in journal (Refereed)
    Abstract [en]

    The accelerated weight histogram method is an enhanced sampling technique used to explore free energy landscapes by applying an adaptive bias. The method is general and easy to extend. Herein, we show how it can be used to efficiently sample alchemical transformations, commonly used for, e.g., solvation and binding free energy calculations. We present calculations and convergence of the hydration free energy of testosterone, representing drug-like molecules. We also include methane and ethanol to validate the results. The protocol is easy to use, does not require a careful choice of parameters, and scales well to accessible resources, and the results converge at least as quickly as when using conventional methods. One benefit of the method is that it can easily be combined with other reaction coordinates, such as intermolecular distances.

  • 38.
    Lundborg, Magnus
    et al.
    ERCO Pharma AB, 11439, Stockholm, Sweden.
    Lidmar, Jack
    KTH, School of Engineering Sciences (SCI), Physics, Condensed Matter Theory.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    On the Path to Optimal Alchemistry2023In: The Protein Journal, ISSN 1572-3887, E-ISSN 1875-8355, Vol. 42, no 5, p. 477-489Article in journal (Refereed)
    Abstract [en]

    Alchemical free energy calculations have become a standard and widely used tool, in particular for calculating and comparing binding affinities of drugs. Although methods to compute such free energies have improved significantly over the last decades, the choice of path between the end states of interest is usually still the same as two decades ago. We will show that there is a fundamentally arbitrary, implicit choice of parametrization of this path. To address this, the notion of the length of a path or a metric is required. A metric recently introduced in the context of the accelerated weight histogram method also proves to be very useful here. We demonstrate that this metric can not only improve the efficiency of sampling along a given path, but that it can also be used to improve the actual choice of path. For a set of relevant use cases, the combination of these improvements can increase the efficiency of alchemical free energy calculations by up to a factor 16.

  • 39.
    Lundborg, Magnus
    et al.
    ERCO Pharma AB, Sci Life Lab, Solna, Sweden..
    Wennberg, Christian
    ERCO Pharma AB, Sci Life Lab, Solna, Sweden..
    Lidmar, Jack
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, School of Engineering Sciences (SCI), Physics, Condensed Matter Theory.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Dept Biophys & Biochem, Sci Life Lab, Solna, Sweden..
    Norlen, Lars
    Karolinska Inst, Dept Cell & Mol Biol CMB, Stockholm, Sweden.;Karolinska Univ Hosp, Dermatol Clin, Stockholm, Sweden..
    Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates2022In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 121, no 20, p. 3837-3849Article in journal (Refereed)
    Abstract [en]

    A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin's barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calc mean square difference was 0.9 cm(2) h(-2)

  • 40.
    Lācis, Uǧis
    et al.
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. FOTONIKA-LV, Institute of Atomic Physics and Spectroscopy, University of Latvia, LV-1586Riga, Latvia.
    Pellegrino, Michele
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sundin, Johan
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Amberg, Gustav
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. Södertorn University, Stockholm, Sweden.
    Zaleski, Stephane
    Sorbonne Université and CNRS, Institut Jean Le Rond ’Alembert, Paris, France Institut Universitaire de France, Paris, France.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Bagheri, Shervin
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Nanoscale sheared droplet: volume-of-fluid, phase-field and no-slip molecular dynamics2022In: Journal of Fluid Mechanics, ISSN 0022-1120, E-ISSN 1469-7645, Vol. 940, article id A10Article in journal (Refereed)
    Abstract [en]

    The motion of the three-phase contact line between two immiscible fluids and a solid surface arises in a variety of wetting phenomena and technological applications. One challenge in continuum theory is the effective representation of molecular motion close to the contact line. Here, we characterize the molecular processes of the moving contact line to assess the accuracy of two different continuum two-phase models. Specifically, molecular dynamics simulations of a two-dimensional droplet between two moving plates are used to create reference data for different capillary numbers and contact angles. We use a simple-point-charge/extended water model. This model provides a very small slip and a more realistic representation of the molecular physics than Lennard-Jones models. The Cahn–Hilliard phase-field model and the volume-of-fluid model are calibrated against the drop displacement from molecular dynamics reference data. It is shown that the calibrated continuum models can accurately capture droplet displacement and droplet break-up for different capillary numbers and contact angles. However, we also observe differences between continuum and atomistic simulations in describing the transient and unsteady droplet behaviour, in particular, close to dynamical wetting transitions. The molecular dynamics of the sheared droplet provide insight into the line friction experienced by the advancing and receding contact lines. The presented results will serve as a stepping stone towards developing accurate continuum models for nanoscale hydrodynamics.

  • 41.
    Pall, Szilard
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Electrical Engineering and Computer Science (EECS), Centres, Centre for High Performance Computing, PDC.
    Zhmurov, Artem
    KTH, School of Electrical Engineering and Computer Science (EECS), Centres, Centre for High Performance Computing, PDC. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Bauer, Paul
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Abraham, Mark James
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Lundborg, Magnus
    ERCO Pharma AB, Stockholm, Sweden..
    Gray, Alan
    NVIDIA Corp, Reading, Berks, England..
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden..
    Heterogeneous parallelization and acceleration of molecular dynamics simulations in GROMACS2020In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 153, no 13, article id 134110Article in journal (Refereed)
    Abstract [en]

    The introduction of accelerator devices such as graphics processing units (GPUs) has had profound impact on molecular dynamics simulations and has enabled order-of-magnitude performance advances using commodity hardware. To fully reap these benefits, it has been necessary to reformulate some of the most fundamental algorithms, including the Verlet list, pair searching, and cutoffs. Here, we present the heterogeneous parallelization and acceleration design of molecular dynamics implemented in the GROMACS codebase over the last decade. The setup involves a general cluster-based approach to pair lists and non-bonded pair interactions that utilizes both GPU and central processing unit (CPU) single instruction, multiple data acceleration efficiently, including the ability to load-balance tasks between CPUs and GPUs. The algorithm work efficiency is tuned for each type of hardware, and to use accelerators more efficiently, we introduce dual pair lists with rolling pruning updates. Combined with new direct GPU-GPU communication and GPU integration, this enables excellent performance from single GPU simulations through strong scaling across multiple GPUs and efficient multi-node parallelization.

  • 42.
    Pellegrino, Michele
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Asymmetry of wetting and de-wetting on high-friction surfaces originates from the same molecular physics2022In: Physics of fluids, ISSN 1070-6631, E-ISSN 1089-7666, Vol. 34, no 10, p. 102010-, article id 102010Article in journal (Refereed)
    Abstract [en]

    Motion of three-phase contact lines is one of the most relevant research topics of micro- and nano-fluidics. According to many hydrodynamic and molecular models, the dynamics of contact lines is assumed overdamped and dominated by localized liquid-solid friction, entailing the existence of a mobility relation between contact line speed and microscopic contact angle. We present and discuss a set of non-equilibrium atomistic molecular dynamics simulations of water nanodroplets spreading on or confined between silica-like walls, showing the existence of the aforementioned relation and its invariance under wetting modes ( "spontaneous " or "forced "). Upon changing the wettability of the walls, it has been noticed that more hydrophilic substrates are easier to wet rather than de-wet; we show how this asymmetry can be automatically captured by a contact line friction model that accounts for the molecular transport between liquid layers. A simple examination of the order and orientation of near-contact-line water molecules corroborates the physical foundation of the model. Furthermore, we present a way to utilize the framework of multicomponent molecular kinetic theory to analyze molecular contributions to the motion of contact lines. Finally, we propose an approach to discriminate between contact line friction models which overcomes the limitations of experimental resolution. This work constitutes a stepping stone toward demystifying wetting dynamics on high-friction hydrophilic substrates and underlines the relevance of contact line friction in modeling the motion of three-phase contact lines.

  • 43.
    Pellegrino, Michele
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. 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. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Near-wall depletion and layering affect contact line friction of multicomponent liquids2024In: Physical Review Fluids, E-ISSN 2469-990X, Vol. 9, no 3, article id 034002Article in journal (Refereed)
    Abstract [en]

    The main causes of energy dissipation in micro- and nanoscale wetting are viscosity and liquid-solid friction localized in the three-phase contact line region. Theoretical models predict the contact line friction coefficient to correlate with the shear viscosity of the wetting fluid. Experiments conducted to investigate such correlation have not singled out a unique scaling law between the two coefficients. We perform molecular dynamics simulations of liquid water-glycerol droplets wetting silicalike surfaces, aimed to demystify the effect of viscosity on contact line friction. The viscosity of the fluid is tuned by changing the relative mass fraction of glycerol in the mixture and it is estimated both via equilibrium and nonequilibrium molecular dynamics simulations. Contact line friction is measured directly by inspecting the velocity of the moving contact line and the microscopic contact angle. It is found that the scaling between contact line friction and viscosity is sublinear, contrary to the prediction of molecular kinetic theory. The disagreement is explained by accounting for the depletion of glycerol in the near-wall region. A correction is proposed, based on multicomponent molecular kinetic theory and the definition of a rescaled interfacial friction coefficient.

  • 44.
    Pellegrino, Michele
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kunchi Kannan, Parvathy
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Bagheri, Shervin
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics.
    Tammisola, Outi
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics.
    Hess, Berk
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Cahn-Hilliard phase-field modeling captures the nanoscale hydrodynamics of contact lines on high-friction surfacesManuscript (preprint) (Other academic)
    Abstract [en]

    Incorporating molecular scale effects in the description of contact lines is difficult but necessary in order to accurately account for all sources of energy dissipation in wetting dynamics. This  holds particularly true in the cases where contact line friction determines wetting dynamics and hydrodynamics models struggle to find a regularisation due to the negligible slip of the wetting liquid over the solid surface. We perform Molecular Dynamics simulations of water/hexane biphasic systems, in the two-phase Couette flow configuration. Wetting occurs over a no-slip silica-like surface with variable wettability. The simulation results are reproduced by a Cahn-Hilliard Navier-Stokes model, which includes localised contact line slip and contact angle dynamics. The continuous equations are directly parametrized from Molecular Dynamics simulation results, under the assumption of the numerical sharp interface limit. The reconfiguration of the liquid/liquid interface and the flow structure are found to be in good quantitative agreement. In particular, interface bending due to viscous flow and contact line friction is fully reproduced. Navier slip is calibrated to ensure numerical stability. The viable combinations of Navier slip and Cahn-Hilliard mobility parameters that agree with Molecular Dynamics simulations in the sharp interface limit are reported and discussed. The results presented in this article indicate that Phase Field modeling can capture the effects of molecular processes on the mobility of contact lines and that an accurate determination of contact line friction is key to fully reproduce Molecular Dynamics simulations.

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  • 45.
    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.

  • 46.
    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.

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  • 47.
    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.

  • 48.
    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.

  • 49.
    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.

  • 50.
    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.

12 1 - 50 of 66
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