Contact Order Dependent Protein Folding Rates: Kinetic Consequences of a Cooperative Interplay Between Favorable Nonlocal Interactions and Local Conformational Preferences

TL;DR

This study uses lattice protein models to demonstrate that the correlation between contact order and folding rates arises from cooperative interactions favoring native-like conformations, explaining empirical observations in small proteins.

Contribution

It introduces a new interaction scheme showing how nonlocal and local interactions cooperatively influence folding rates and reproduce experimental kinetic features.

Findings

Folding rates are highly correlated with contact order (r=0.914).

Models exhibit calorimetric cooperativity similar to real proteins.

The scheme spans over 2.5 orders of magnitude in folding rates.

Abstract

Physical mechanisms underlying the empirical correlation between relative contact order (CO) and folding rate among naturally-occurring small single-domain proteins are investigated by evaluating postulated interaction schemes for a set of three-dimensional 27mer lattice protein models with 97 different CO values. Many-body interactions are constructed such that contact energies become more favorable when short chain segments sequentially adjacent to the contacting residues adopt native-like conformations. At a given interaction strength, this scheme leads to folding rates that are logarithmically well correlated with CO (correlation coefficient $r=0.914$) and span more than 2.5 orders of magnitude, whereas folding rates of the corresponding G\=o models with additive contact energies have much less logarithmic correlation with CO and span only approximately one order of magnitude. The present protein chain models also exhibit calorimetric cooperativity and linear chevron plots similar to that observed experimentally for proteins with apparent simple two-state folding/unfolding kinetics. Thus, our findings suggest that CO-dependent folding rates of real proteins may arise partly from a significant positive coupling between nonlocal contact favorabilities and local conformational preferences.