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FF12MC: A revised AMBER forcefield and new protein simulation protocol.

ABSTRACT: Specialized to simulate proteins in molecular dynamics (MD) simulations with explicit solvation, FF12MC is a combination of a new protein simulation protocol employing uniformly reduced atomic masses by tenfold and a revised AMBER forcefield FF99 with (i) shortened C?H bonds, (ii) removal of torsions involving a nonperipheral sp(3) atom, and (iii) reduced 1-4 interaction scaling factors of torsions ? and ?. This article reports that in multiple, distinct, independent, unrestricted, unbiased, isobaric-isothermal, and classical MD simulations FF12MC can (i) simulate the experimentally observed flipping between left- and right-handed configurations for C14-C38 of BPTI in solution, (ii) autonomously fold chignolin, CLN025, and Trp-cage with folding times that agree with the experimental values, (iii) simulate subsequent unfolding and refolding of these miniproteins, and (iv) achieve a robust Z score of 1.33 for refining protein models TMR01, TMR04, and TMR07. By comparison, the latest general-purpose AMBER forcefield FF14SB locks the C14-C38 bond to the right-handed configuration in solution under the same protein simulation conditions. Statistical survival analysis shows that FF12MC folds chignolin and CLN025 in isobaric-isothermal MD simulations 2-4 times faster than FF14SB under the same protein simulation conditions. These results suggest that FF12MC may be used for protein simulations to study kinetics and thermodynamics of miniprotein folding as well as protein structure and dynamics. Proteins 2016; 84:1490-1516. © 2016 The Authors Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

SUBMITTER: Pang YP

PROVIDER: S-EPMC5129589 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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FF12MC: A revised AMBER forcefield and new protein simulation protocol.

Pang Yuan-Ping YP

Proteins 20160721 10

Specialized to simulate proteins in molecular dynamics (MD) simulations with explicit solvation, FF12MC is a combination of a new protein simulation protocol employing uniformly reduced atomic masses by tenfold and a revised AMBER forcefield FF99 with (i) shortened CH bonds, (ii) removal of torsions involving a nonperipheral sp(3) atom, and (iii) reduced 1-4 interaction scaling factors of torsions ϕ and ψ. This article reports that in multiple, distinct, independent, unrestricted, unbiased, iso ...[more]

PMID: 27348292

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Project description:In this work, we introduce Forcefield_PTM, a set of AMBER forcefield parameters consistent with ff03 for 32 common post-translational modifications. Partial charges were calculated through ab initio calculations and a two-stage RESP-fitting procedure in an ether-like implicit solvent environment. The charges were found to be generally consistent with others previously reported for phosphorylated amino acids, and trimethyllysine, using different parameterization methods. Pairs of modified and their corresponding unmodified structures were curated from the PDB for both single and multiple modifications. Background structural similarity was assessed in the context of secondary and tertiary structures from the global dataset. Next, the charges derived for Forcefield_PTM were tested on a macroscopic scale using unrestrained all-atom Langevin molecular dynamics simulations in AMBER for 34 (17 pairs of modified/unmodified) systems in implicit solvent. Assessment was performed in the context of secondary structure preservation, stability in energies, and correlations between the modified and unmodified structure trajectories on the aggregate. As an illustration of their utility, the parameters were used to compare the structural stability of the phosphorylated and dephosphorylated forms of OdhI. Microscopic comparisons between quantum and AMBER single point energies along key ? torsions on several PTMs were performed and corrections to improve their agreement in terms of mean squared errors and squared correlation coefficients were parameterized. This forcefield for post-translational modifications in condensed-phase simulations can be applied to a number of biologically relevant and timely applications including protein structure prediction, protein and peptide design, docking, and to study the effect of PTMs on folding and dynamics. We make the derived parameters and an associated interactive webtool capable of performing post-translational modifications on proteins using Forcefield_PTM available at http://selene.princeton.edu/FFPTM.

Dataset Information

FF12MC: A revised AMBER forcefield and new protein simulation protocol.

Publications

FF12MC: A revised AMBER forcefield and new protein simulation protocol.

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