Effect of gatekeepers on the early folding kinetics of a model β-barrel protein

Abstract

Recent exciting experimental observations have suggested the existence of gatekeeper residues in protein folding. These residues may influence only slightly the stabilization of a protein’s final folded state, but have an important kinetic function in the early stages of folding—to avoid nonproductive folding routes. We explore the physical mechanism for the action of such gatekeepers, in the form of salt-bridgelike charged residues, on the early folding behavior of a model 46-mer β-barrel protein. Computer simulations employing Langevin dynamics show that the gatekeepers enhance the kinetics of folding on time scales that are about three orders of magnitude shorter than previously reported folding times for this model system. Analysis of the unfolded ensembles of the wild type (WT) β-barrel and several good and poor salt bridge designs indicates that the proteins with well designed salt-bridge gatekeepers favor productive folding routes when compared to the WT system. The conclusions of our theoretical observations are in agreement with experimental studies of the ribosomal protein S6 and its mutants.