A combined maximum-caliber and FEP approach to predict how mutations perturb protein stability and folding kinetics

Abstract

Over the last decade, computational protein design has mainly focused on estimating changes in protein stability using molecular dynamics-based alchemical free energy methods such as free energy perturbation (FEP) and thermodynamic integration (TI). Much less attention has been paid to predicting folding kinetics, due to the complexity of the reaction and difficulty in conformational sampling on slow timescales. Yet, the ability to predict changes to folding kinetics would be highly valuable, both for determining biological function and for computational design.