Evaluation and Improvement of the Amber ff99SB Force Field with an Advanced Water Model

Abstract

A recurring concern when studying biomolecules with molecular dynamics (MD) simulations is the accuracy of the underlying force field and solvent model. These considerations are especially relevant for simulations of intrinsically disordered peptides and proteins, for which energy differences between conformations are small and interactions with water are enhanced. In this work, we investigate the accuracy of the AMBER ff99SB force field, combined with either the TIP3P or the TIP4P-Ew water model, using both conventional MD and replica exchange MD (REMD) simulations to generate conformational ensembles for (disordered) trialanine, triglycine, and trivaline peptides.We find that the TIP4P-Ew water model yields significantly better agreement with experimentally measured scalar couplings - and therefore more accurate conformational ensembles - for both trialanine and triglycine. For trivaline, however, we find that the TIP3P and TIP4P-Ew ensembles are equivalent in accuracy. To address this discrepancy and further improve the force field, we derive new van der Waals parameters for alkanes in TIP4P-Ew water and a straightforward perturbation to the f backbone dihedral potential that shifts the β-PPII equilibrium. Of the two, we find that the revised f backbone dihedral potential is more effective and yields significantly improved conformational ensembles for both the trialanine and trivaline peptides in TIP4P-Ew water.