Simulating Protein Fold Switching by Replica Exchange with Tunneling

Abstract

Recent experiments suggest that an amino acid sequence encodes not only the native fold of a protein but also other forms that are essential for its function or are important during folding or association. These various forms populate a multifunnel folding and association landscape where mutations, changes in environment, or interaction with other molecules switch between the encoded folds. We introduce replica exchange with tunneling as a way to efficiently simulate switching between distinct folds of proteins and protein aggregates. The correctness and efficiency of our approach are demonstrated in a series of simulations covering a wide range of proteins, from a small 11-residue large designed peptide to two 56-residue large mutants of the A and B domains of protein G.