A fully atomistic computer simulation study of cold denaturation of a β-hairpin

Cold denaturation is a fundamental phenomenon in aqueous solutions where the native structure of proteins disrupts on cooling. Understanding this process in molecular details can provide a new insight into the detailed natures of hydrophobic forces governing the stability of proteins in water. We show that the cold-denaturation-like phenomenon can be directly observed at low temperatures using a fully atomistic molecular dynamics simulation method. Using a highly optimized protein force field in conjunction with three different explicit water models, a replica exchange molecular dynamics simulation scheme at constant pressures allows for the computation of the melting profile of an experimentally well-characterized β-hairpin peptide. For all three water models tested, the simulated melting profiles are indicative of possible cold denaturation. From the analysis of simulation ensembles, we find that the most probable cold-denatured structure is structurally compact, with its hydrogen bonds and native hydrophobic packing substantially disrupted.