Observations on AMBER Force Field Performance under the Conditions of Low pH and High Salt Concentrations

Molecular dynamics simulations have become an important tool for the study of structures, dynamics, and functions of biomolecules. Time scales and force field accuracy are key factors for the reliability of these simulations. With the advancement of computational platforms and simulation technologies, all-atom simulations of proteins in explicitly represented aqueous solutions can reach as long as milliseconds. However, there are indications of minor force field flaws in literature. In this work we present our observations on force field accuracy under uncommon conditions. We performed molecular dynamics simulations of BBL refolding in aqueous solutions of acidic pH and high salt concentrations (up to 6 M) with the AMBER99SB-ILDN force field for a microsecond time scale. The reliability of the simulations relies on the accuracy of the physical models of protein, water, and ions. Our simulations show the same trend as experiments: higher salt concentration facilities refolding. However, we have observed the presence of β-sheet in the native helical region as well as α-helix and β-sheet in the native loop region. Some of the nonnative secondary structures are even more stable than native helices. Aside from the secondary structure issue under the uncommon conditions, we have found that the rigidity of glycine dihedral angles in the loop region leads to low root-mean-square deviations but large topological differences from the native structure. Whether this is due to a force field deficiency or not needs further investigations. Recently developed ion parameters exhibit evident liquid features even in the 6 M LiCl solution. However, cation-anion interactions in TIP3P water still seem too strong, leading to high fractions of contact ion pairs. We do not find any specific ion-binding motif, thus we conclude that the effect of salt is a nonspecific electrostatic screening in our simulations. Our observations on the AMBER force field performance under acidic conditions and high salt concentrations show that simulations under extreme conditions can provide informative tests of physical models.