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

TL;DR

This study uses a coarse-grained variational model to predict protein folding rates, emphasizing the importance of excluded volume effects and native topology, and finds consistent prefactors across diverse proteins.

Contribution

The paper introduces a model incorporating excluded volume effects that accurately predicts folding rates and elucidates the role of native topology and structural cooperativity in protein folding.

Findings

Folding rate predictions are reliable when including excluded volume effects.

Folding routes with higher cooperativity have sharper interfaces and higher energy barriers.

Prefactors are relatively uniform across different small two-state proteins.

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 non-uniformly across the set of protein studied. Neverthless, the calculated prefactors k0 are found to be relatively uniform across the protein set, with variation in 1/k0 less than a factor of five. 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 30ns, we find that 1/k0 (1-5)us (with average 1/k0 4us). 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.