Why Do Protein Folding Rates Correlate with Metrics of Native Topology?

Patrícia F. N. Faísca,Antonio Rey,Rui D. M. Travasso,Andrea Parisi,Salvador Ventura

doi:10.1371/journal.pone.0035599

Abstract

For almost 15 years, the experimental correlation between protein folding rates and the contact order parameter has been under scrutiny. Here, we use a simple simulation model combined with a native-centric interaction potential to investigate the physical roots of this empirical observation. We simulate a large set of circular permutants, thus eliminating dependencies of the folding rate on other protein properties (e.g. stability). We show that the rate-contact order correlation is a consequence of the fact that, in high contact order structures, the contact order of the transition state ensemble closely mirrors the contact order of the native state. This happens because, in these structures, the native topology is represented in the transition state through the formation of a network of tertiary interactions that are distinctively long-ranged.

Highlights

The notion that form and function are intimately related is an old one in biology
In the late 1990’s, Plaxco and co-workers made the serendipitous observation that a parameter named contact order (CO), measuring the average sequence separation between all pairs of residues within physical contact in the native structure, is highly correlated with the logarithmic folding rates of small, single domain proteins that fold in a two-state manner [1]
If one considers that the protein folding process follows the transition state (TS) theory, the folding rate should be related to the free energy barrier separating the denatured ensemble from the transition state ensemble (TSE) at a given folding temperature, and it should not be directly linked to the native structure

Summary

Introduction

The notion that form and function are intimately related is an old one in biology. In his seminal work ‘‘On Growth and Form’’, D’Arcy Thomson explored the relation between natural geometries, the dynamics of growth and physical processes in living systems. If one considers that the protein folding process follows the transition state (TS) theory, the folding rate should be related to the free energy barrier separating the denatured ensemble from the transition state ensemble (TSE) at a given folding temperature, and it should not be directly linked to the native structure.

Results

Conclusion