Microscopic theory of critical folding nuclei and reconfiguration activation barriers in folding proteins

Abstract

An explicit droplet calculation is developed to address two aspects of the folding kinetics of large proteins: the thermodynamic folding barrier and the reconfiguration rate. First, a nonspecific folding nucleus is described as the instanton or dropletsolution of a free energy functional derived for a minimally frustrated polymer Hamiltonian of the Gō type. Second, a theory for the barriers for transitions between trapped misfolded states is developed using a replica approach extended to inhomogeneous cases near the glass transition temperature of a random heteropolymer. Replica instantons are computed and their shape described. These two factors are then combined to give a microscopic theory of the folding time.