Are AMBER Force Fields and Implicit Solvation Models Additive? A Folding Study with a Balanced Peptide Test Set

Abstract

Implicit solvation models have long been sought as routes to significantly increase the speed and capabilities of biomolecular simulations. However, it has not always been clear that force fields developed independently of solvation models can together accurately predict secondary structure and folding, and whether the separate influences of the solvation and force field models can be described as independent and additive (versus synergistic). Here, we test two implicit solvation models with several recently developed protein force fields, within the AMBER simulation package. We create a representative set of five helical and five hairpin peptides, 11-20 amino acid residues in length, and calculate folded structures using replica exchange molecular dynamics simulations for all force field/solvent/peptide combinations, each with two instances using distinct starting configurations. In general, we find that no force field/solvent combination successfully folds all peptides and that the hairpin peptides are more difficult to capture. That being said, the older ff96/igb5* combination does a reasonable job in folding multiple secondary structures, while ff14SB/igb5* and ff14ipq/igb8 work well for helical and hairpin motifs, respectively. All combinations give rise to similar numbers of salt bridges, except for solvent models paired with ff14ipq, which slightly enhances them. Interestingly, we are unable statistically to decouple the effects of force field, solvent model, and peptide secondary structure on performance, such that particular combinations can have specific effects. These results suggest that future efforts might benefit from codevelopment of implicit models with force fields or from the use of emerging coarse-graining strategies that extract solvation effects in a bottom-up manner.