OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials.

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy.

OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials.

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy.

AmberTools.

AmberTools is a free and open-source collection of programs used to set up, run, and analyze molecular simulations. The newer features contained within AmberTools23 are briefly described in this Application note.

Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix.

The refinement of biomolecular crystallographic models relies on geometric restraints to help to address the paucity of experimental data typical in these experiments. Limitations in these restraints can degrade the quality of the resulting atomic models. Here, an integration of the full all-atom Amber molecular-dynamics force field into Phenix crystallographic refinement is presented, which enables more complete modeling of biomolecular chemistry.

A Coupled Ionization-Conformational Equilibrium Is Required To Understand the Properties of Ionizable Residues in the Hydrophobic Interior of Staphylococcal Nuclease.

Ionizable residues in the interior of proteins play essential roles, especially in biological energy transduction, but are relatively rare and seem incompatible with the complex and polar environment. We perform a comprehensive study of the internal ionizable residues on 21 variants of staphylococcal nuclease with internal Lys, Glu, or Asp residues. Using pH replica exchange molecular dynamics simulations, we find that, in most cases, the pK values of these internal ionizable residues are shifted significantly from their values in solution.

Improved Accuracy for Constant pH-REMD Simulations through Modification of Carboxylate Effective Radii.

The accuracy of computational models for simulating biomolecules under specific solution pH conditions is critical for properly representing the effect of pH in biological processes. Constant pH (CpH) simulations involving implicit solvent using the AMBER software often incorrectly estimate pK values of aspartate and glutamate residues due to large effective radii stemming from the presence of dummy protons. These inaccuracies stem from problems in the sampled ensembles of titratable residues that can influence other observable pH-dependent behavior, such as conformational change.

OpenMM 7: Rapid development of high performance algorithms for molecular dynamics.

OpenMM is a molecular dynamics simulation toolkit with a unique focus on extensibility. It allows users to easily add new features, including forces with novel functional forms, new integration algorithms, and new simulation protocols. Those features automatically work on all supported hardware types (including both CPUs and GPUs) and perform well on all of them.

Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset.

We describe our efforts to prepare common starting structures and models for the SAMPL5 blind prediction challenge. We generated the starting input files and single configuration potential energies for the host-guest in the SAMPL5 blind prediction challenge for the GROMACS, AMBER, LAMMPS, DESMOND and CHARMM molecular simulation programs. All conversions were fully automated from the originally prepared AMBER input files using a combination of the ParmEd and InterMol conversion programs.

Advanced Potential Energy Surfaces for Molecular Simulation.

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms.

CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field.

Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM.

MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories.

As molecular dynamics (MD) simulations continue to evolve into powerful computational tools for studying complex biomolecular systems, the necessity of flexible and easy-to-use software tools for the analysis of these simulations is growing. We have developed MDTraj, a modern, lightweight, and fast software package for analyzing MD simulations. MDTraj reads and writes trajectory data in a wide variety of commonly used formats.

AFNMR: automated fragmentation quantum mechanical calculation of NMR chemical shifts for biomolecules.

We evaluate the performance of the automated fragmentation quantum mechanics/molecular mechanics approach (AF-QM/MM) on the calculation of protein and nucleic acid NMR chemical shifts. The AF-QM/MM approach models solvent effects implicitly through a set of surface charges computed using the Poisson-Boltzmann equation, and it can also be combined with an explicit solvent model through the placement of water molecules in the first solvation shell around the solute; the latter substantially improves the accuracy of chemical shift prediction of protons involved in hydrogen bonding with solvent. We also compare the performance of AF-QM/MM on proteins and nucleic acids with two leading empirical chemical shift prediction programs SHIFTS and SHIFTX2.

Interpretation of pH-activity profiles for acid-base catalysis from molecular simulations.

The measurement of reaction rate as a function of pH provides essential information about mechanism. These rates are sensitive to the pK(a) values of amino acids directly involved in catalysis that are often shifted by the enzyme active site environment. Experimentally observed pH-rate profiles are usually interpreted using simple kinetic models that allow estimation of "apparent pK(a)" values of presumed general acid and base catalysts.

Constant pH Replica Exchange Molecular Dynamics in Explicit Solvent Using Discrete Protonation States: Implementation, Testing, and Validation.

By utilizing Graphics Processing Units, we show that constant pH molecular dynamics simulations (CpHMD) run in Generalized Born (GB) implicit solvent for long time scales can yield poor p predictions as a result of sampling unrealistic conformations. To address this shortcoming, we present a method for performing constant pH molecular dynamics simulations (CpHMD) in explicit solvent using a discrete protonation state model. The method involves standard molecular dynamics (MD) being propagated in explicit solvent followed by protonation state changes being attempted in GB implicit solvent at fixed intervals.

Multidimensional Replica Exchange Molecular Dynamics Yields a Converged Ensemble of an RNA Tetranucleotide.

A necessary step to properly assess and validate the performance of force fields for biomolecules is to exhaustively sample the accessible conformational space, which is challenging for large RNA structures. Given questions regarding the reliability of modeling RNA structure and dynamics with current methods, we have begun to use RNA tetranucleotides to evaluate force fields. These systems, though small, display considerable conformational variability and complete sampling with standard simulation methods remains challenging.

SPAM: A Simple Approach for Profiling Bound Water Molecules.

A method that identifies the hydration shell structure of proteins and estimates the relative free energies of water molecules within that hydration shell is described. The method, which we call "SPAM" (maps spelled in reverse), utilizes explicit solvent molecular dynamics (MD) simulations to capture discrete hydration sites at the water-protein interface and computes a local free energy measure from the distribution of interaction energies between water and the environment at a specific site. SPAM is able to provide a qualitative estimate of the thermodynamic profile of bound water molecules that correlates nicely with well-studied structure-activity relationships and observed binding "hot spots".

Enhancing Conformation and Protonation State Sampling of Hen Egg White Lysozyme Using pH Replica Exchange Molecular Dynamics.

We evaluate the efficiency of the pH replica exchange molecular dynamics (pH-REMD) method proposed by Itoh et al. (Proteins2011, 79, 3420-3436) by using it to predict the pKa values of the titratable residues in hen egg white lysozyme (HEWL). pKa values predicted using pH-REMD converge significantly faster than those calculated using constant pH molecular dynamics (CpHMD).

MMPBSA.py: An Efficient Program for End-State Free Energy Calculations.

MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations.

pH-dependent mechanism of nitric oxide release in nitrophorins 2 and 4.

Nitrophorins are NO carrier proteins that transport and release NO through a pH-dependent conformational change. They bind NO tightly in a low pH environment and release it in a higher pH environment. Experimental evidence shows that the increase in the NO dissociation equilibrium constant, K(d), is due mainly to an increase in the NO release rate.