Theory and experiment on enthalpic barriers and specific nonnative interactions in cooperative protein folding

PHYS 97

Hue Sun Chan, chan@arrhenius.med.toronto.edu, Departments of Biochemistry and of Molecular Genetics, University of Toronto, 1 King's College Circle, Medical Sciences Building 5th Floor, Toronto, ON M5S 1A8, Canada
The traditional formulation of folding transition states entails a macroscopic folding free energy barrier with a significantly positive enthalpic component. This represents a potential objection to the funnel picture of protein folding, because enthalpic barriers might indicate substantial uphill moves even along microscopic folding trajectories. Using extensive atomic simulations, we resolved the paradox by pointing to a dramatic entropy-enthalpy compensation due to steric dewetting at the rate-limiting step of folding. Previous stuides have suggested a significant role for nonnative interactions in protein folding as well. Using a new coarse-grained chain model, we predicted specific nonnative interactions that accelerate or decelerate folding of Fyn SH3 mutants, depending on whether the nonnative contacts are more populated in the transition state or unfolded state. These predictions were subsequently corroborated by double mutant cycle experiments, demonstrating that certain kinetically important nonnative interactions are predicable by a simple consideration of hydrophobicity.