Residue-specific force field based on the protein coil library. RSFF1: modification of OPLS-AA/L

Traditional protein force fields use one set of parameters for most of the 20 amino acids (AAs), allowing transferability of the parameters. However, a significant shortcoming is the difficulty to fit the Ramachandran plots of all AA residues simultaneously, affecting the accuracy of the force field. In this Feature Article, we report a new strategy for protein force field parametrization. Backbone and side-chain conformational distributions of all 20 AA residues obtained from protein coil library were used as the target data. The dihedral angle (torsion) potentials and some local nonbonded (1-4/1-5/1-6) interactions in OPLS-AA/L force field were modified such that the target data can be excellently reproduced by molecular dynamics simulations of dipeptides (blocked AAs) in explicit water, resulting in a new force field with AA-specific parameters, RSFF1. An efficient free energy decomposition approach was developed to separate the corrections on ϕ and ψ from the two-dimensional Ramachandran plots. RSFF1 is shown to reproduce the experimental NMR (3)J-coupling constants of AA dipeptides better than other force fields. It has a good balance between α-helical and β-sheet secondary structures. It can successfully fold a set of α-helix proteins (Trp-cage and Homeodomain) and β-hairpins (Trpzip-2, GB1 hairpin), which cannot be consistently stabilized by other state-of-the-art force fields. Interestingly, the RSFF1 force field systematically overestimates the melting temperature (and the stability of native state) of these peptides/proteins. It has a potential application in the simulation of protein folding and protein structure refinement.