Reliable protein folding on nonfunneled energy landscapes: The free energy reaction path

PHYS 99

Corey O'Hern, corey.ohern@yale.edu1, Jerzy Blawzdziewicz, jerzy.blawzdziewicz@yale.edu2, and Gregg Lois, gregg.lois@yale.edu1. (1) Department of Mechanical Engineering, Yale University, P. O. Box 208286, New Haven, CT 06520-8286, (2) Mechanical Engineering, Yale University, P.O. Box 208286, New Haven, CT 06520-8286
A theoretical framework is developed to study the dynamics of protein folding. The key insight is that the search for the native protein conformation is influenced by the rate r at which external parameters, such as temperature, chemical denaturant or pH, are adjusted to induce folding. A theory based on this insight predicts that (1) proteins with non-funneled energy landscapes can fold reliably to their native state, (2) reliable folding can occur as an equilibrium or out-of-equilibrium process, and (3) reliable folding only occurs when the rate r is below a limiting value, which can be calculated from measurements of the free energy. We test these predictions against numerical simulations of model proteins with a single energy scale.