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Residue-Specific Force Field (RSFF2) Improves the Modeling of Conformational Behavior of Peptides and Proteins.

ABSTRACT: A recent report of (3)J(HNH?) scalar coupling constants for hundreds of two-residue peptides has provided an important opportunity to test simulation force fields for proteins. Here, we compare the abilities of three derivatives of the Amber ff99SB force field to reproduce these data. We report molecular dynamics (MD) simulations of 256 two-residue peptides and show that the recently developed residue-specific force field (RSFF2) produces a dramatic improvement in the agreement with experimental (3)J(HNH?) coupling constants. We further show that RSFF2 also appears to produce a modest improvement in reproducing the (3)J(HNH?) coupling constants of five model proteins. Perhaps surprisingly, an analysis of neighboring residue effects (NREs) on the (3)J(HNH?) coupling constants of the two-residue peptides indicates little difference between the force fields' abilities to reproduce experimental NREs. We speculate that this might indicate limitations in the force fields' descriptions of nonbonded interactions between adjacent side chains or with terminal capping groups.

SUBMITTER: Li S

PROVIDER: S-EPMC4657862 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Residue-Specific Force Field (RSFF2) Improves the Modeling of Conformational Behavior of Peptides and Proteins.

Li Shuxiang S Elcock Adrian H AH

The journal of physical chemistry letters 20150526 11

A recent report of (3)J(HNHα) scalar coupling constants for hundreds of two-residue peptides has provided an important opportunity to test simulation force fields for proteins. Here, we compare the abilities of three derivatives of the Amber ff99SB force field to reproduce these data. We report molecular dynamics (MD) simulations of 256 two-residue peptides and show that the recently developed residue-specific force field (RSFF2) produces a dramatic improvement in the agreement with experimental ...[more]

PMID: 26266514

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Project description:Presented is a polarizable force field based on a classical Drude oscillator framework, currently implemented in the programs CHARMM and NAMD, for modeling and molecular dynamics (MD) simulation studies of peptides and proteins. Building upon parameters for model compounds representative of the functional groups in proteins, the development of the force field focused on the optimization of the parameters for the polypeptide backbone and the connectivity between the backbone and side chains. Optimization of the backbone electrostatic parameters targeted quantum mechanical conformational energies, interactions with water, molecular dipole moments and polarizabilities and experimental condensed phase data for short polypeptides such as (Ala)5. Additional optimization of the backbone φ, ψ conformational preferences included adjustments of the tabulated two-dimensional spline function through the CMAP term. Validation of the model included simulations of a collection of peptides and proteins. This 1st generation polarizable model is shown to maintain the folded state of the studied systems on the 100 ns timescale in explicit solvent MD simulations. The Drude model typically yields larger RMS differences as compared to the additive CHARMM36 force field (C36) and shows additional flexibility as compared to the additive model. Comparison with NMR chemical shift data shows a small degradation of the polarizable model with respect to the additive, though the level of agreement may be considered satisfactory, while for residues shown to have significantly underestimated S2 order parameters in the additive model, improvements are calculated with the polarizable model. Analysis of dipole moments associated with the peptide backbone and tryptophan side chains show the Drude model to have significantly larger values than those present in C36, with the dipole moments of the peptide backbone enhanced to a greater extent in sheets versus helices and the dipoles of individual moieties observed to undergo significant variations during the MD simulations. Although there are still some limitations, the presented model, termed Drude-2013, is anticipated to yield a molecular picture of peptide and protein structure and function that will be of increased physical validity and internal consistency in a computationally accessible fashion.

Dataset Information

Residue-Specific Force Field (RSFF2) Improves the Modeling of Conformational Behavior of Peptides and Proteins.

Publications

Residue-Specific Force Field (RSFF2) Improves the Modeling of Conformational Behavior of Peptides and Proteins.

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