A protocol for preparing explicitly solvated systems for stable molecular dynamics simulations.

Before beginning the production phase of molecular dynamics simulations, i.e., the phase that produces the data to be analyzed, it is often necessary to first perform a series of one or more preparatory minimizations and/or molecular dynamics simulations in order to ensure that subsequent production simulations are stable. This is particularly important for simulations with explicit solvent molecules. Despite the preparatory minimizations and simulations being ubiquitous and essential for stable production simulations, there are currently no general recommended procedures to perform them and very few criteria to decide whether the system is capable of producing a stable simulation trajectory. Here, we propose a simple and well-defined ten step simulation preparation protocol for explicitly solvated biomolecules, which can be applied to a wide variety of system types, as well as a simple test based on the system density for determining whether the simulation is stabilized.

[1]  Jing Huang,et al.  CHARMM36 all‐atom additive protein force field: Validation based on comparison to NMR data , 2013, J. Comput. Chem..

[2]  Jacob D. Durrant,et al.  Molecular dynamics simulations and drug discovery , 2011, BMC Biology.

[3]  Christian Kandt,et al.  Setting up and running molecular dynamics simulations of membrane proteins. , 2007, Methods.

[4]  J. Berg,et al.  Molecular dynamics simulations of biomolecules , 2002, Nature Structural Biology.

[5]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[6]  W. Im,et al.  Automated Builder and Database of Protein/Membrane Complexes for Molecular Dynamics Simulations , 2007, PloS one.

[7]  A. Roitberg,et al.  All-atom structure prediction and folding simulations of a stable protein. , 2002, Journal of the American Chemical Society.

[8]  E. Walton,et al.  Equilibration of experimentally determined protein structures for molecular dynamics simulation. , 2006, Physical review. E, Statistical, nonlinear, and soft matter physics.

[9]  J. Šponer,et al.  Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles , 2011, Journal of chemical theory and computation.

[10]  José Mario Martínez,et al.  PACKMOL: A package for building initial configurations for molecular dynamics simulations , 2009, J. Comput. Chem..

[11]  B. Brooks,et al.  Constant pressure molecular dynamics simulation: The Langevin piston method , 1995 .

[12]  T. Cheatham,et al.  Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations , 2008, The journal of physical chemistry. B.

[13]  F. Ding,et al.  Ab initio folding of proteins with all-atom discrete molecular dynamics. , 2008, Structure.

[14]  D. Case,et al.  PARMBSC1: A REFINED FORCE-FIELD FOR DNA SIMULATIONS , 2015, Nature Methods.

[15]  R. Zhou.  Replica exchange molecular dynamics method for protein folding simulation. , 2007, Methods in molecular biology.

[16]  B. Berne,et al.  The free energy landscape for β hairpin folding in explicit water , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Shirts,et al.  Effects of Temperature Control Algorithms on Transport Properties and Kinetics in Molecular Dynamics Simulations. , 2013, Journal of chemical theory and computation.

[18]  C. Simmerling,et al.  ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. , 2015, Journal of chemical theory and computation.

[19]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[20]  Jianpeng Ma,et al.  CHARMM: The biomolecular simulation program , 2009, J. Comput. Chem..

[21]  F. J. Luque,et al.  Classical molecular interaction potentials: Improved setup procedure in molecular dynamics simulations of proteins , 2001, Proteins.

[22]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[23]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[24]  Alexander D. MacKerell,et al.  CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field , 2015, Journal of chemical theory and computation.

[25]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[26]  V. Cherezov,et al.  Transmembrane peptides stabilize inverted cubic phases in a biphasic length-dependent manner: implications for protein-induced membrane fusion. , 2006, Biophysical journal.

[27]  P. Kollman,et al.  Molecular Modeling of Nucleic Acid Structure: Setup and Analysis , 2014, Current protocols in nucleic acid chemistry.

[28]  R. Dror,et al.  Long-timescale molecular dynamics simulations of protein structure and function. , 2009, Current opinion in structural biology.

[29]  Daniel R Roe,et al.  PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. , 2013, Journal of chemical theory and computation.

[30]  J. Åqvist,et al.  Molecular Dynamics Simulations of Water and Biomolecules with a Monte Carlo Constant Pressure Algorithm , 2004 .

[31]  Niel M. Henriksen,et al.  Reliable oligonucleotide conformational ensemble generation in explicit solvent for force field assessment using reservoir replica exchange molecular dynamics simulations. , 2013, The journal of physical chemistry. B.

[32]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[33]  Rafael C. Bernardi,et al.  Molecular dynamics simulations of large macromolecular complexes. , 2015, Current opinion in structural biology.

[34]  M. Karplus,et al.  Molecular dynamics simulations in biology , 1990, Nature.

[35]  Christopher I. Bayly,et al.  Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validation , 2002, J. Comput. Chem..

[36]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[37]  Josep Ramón Goñi,et al.  Molecular dynamics simulations: advances and applications , 2015, Advances and applications in bioinformatics and chemistry : AABC.

[38]  John D Chodera,et al.  A Simple Method for Automated Equilibration Detection in Molecular Simulations. , 2016, Journal of chemical theory and computation.

[39]  J. Šponer,et al.  Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/γ Conformers , 2007 .

[40]  H. Berendsen,et al.  COMPUTER-SIMULATION OF MOLECULAR-DYNAMICS - METHODOLOGY, APPLICATIONS, AND PERSPECTIVES IN CHEMISTRY , 1990 .

[41]  D. Frenkel,et al.  Molecular dynamics simulations. , 2002, Current opinion in structural biology.

[42]  Alexander D. MacKerell,et al.  Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. , 2010, The journal of physical chemistry. B.

[43]  Steve Plimpton,et al.  Fast parallel algorithms for short-range molecular dynamics , 1993 .

[44]  M. Klein,et al.  Constant pressure molecular dynamics algorithms , 1994 .