Excluded volume, local structural cooperativity, and the polymer physics of protein folding rates.

Abstract

A coarse-grained variational model is used to investigate the polymer dynamics of barrier crossing for a diverse set of two-state folding proteins. The model gives reliable folding rate predictions provided excluded volume terms that induce minor structural cooperativity are included in the interaction potential. In general, the cooperative folding routes have sharper interfaces between folded and unfolded regions of the folding nucleus and higher free energy barriers. The calculated free energy barriers are strongly correlated with native topology as characterized by contact order. Increasing the rigidity of the folding nucleus changes the local structure of the transition state ensemble nonuniformly across the set of proteins studied. Nevertheless, the calculated prefactors k(0) are found to be relatively uniform across the protein set, with variation in 1/k(0) less than a factor of 5. This direct calculation justifies the common assumption that the prefactor is roughly the same for all small two-state folding proteins. Using the barrier heights obtained from the model and the best-fit monomer relaxation time 30 ns, we find that 1/k(0) approximately 1-5 mus (with average 1/k(0) approximately 4 micros). This model can be extended to study subtle aspects of folding such as the variation of the folding rate with stability or solvent viscosity and the onset of downhill folding.