Residue-Specific Force Field Based on Protein Coil Library. RSFF2: Modification of AMBER ff99SB

Recently, we developed a residue-specific force field (RSFF1) based on conformational free-energy distributions of the 20 amino acid residues from a protein coil library. Most parameters in RSFF1 were adopted from the OPLS-AA/L force field, but some van der Waals and torsional parameters that effectively affect local conformational preferences were introduced specifically for individual residues to fit the coil library distributions. Here a similar strategy has been applied to modify the Amber ff99SB force field, and a new force field named RSFF2 is developed. It can successfully fold a-helical structures such as polyalanine peptides, Trp-cage miniprotein, and villin headpiece subdomain and beta-sheet structures such as Trpzip-2, GB1 beta-hairpins, and the WW domain, simultaneously. The properties of various popular force fields in balancing between a-helix and beta-sheet are analyzed based on their descriptions of local conformational features of various residues, and the analysis reveals the importance of accurate local free-energy distributions. Unlike the RSFF1, which overestimates the stability of both alpha-helix and beta-sheet, RSFF2 gives melting curves of alpha-helical peptides and Trp-cage in good agreement with experimental data. Fitting to the two-state model, RSFF2 gives folding enthalpies and entropies in reasonably good agreement with available experimental results.