On the relation between native geometry and conformational plasticity

TL;DR

This study investigates how native protein geometry influences folding plasticity, revealing that structures with more local contacts are more adaptable to mutations than those with many long-range contacts, due to differences in folding cooperativity.

Contribution

It demonstrates a clear relationship between native contact distribution and folding plasticity using lattice protein simulations, highlighting the role of native geometry in folding robustness.

Findings

Local contact-rich structures are more plastic than those with many long-range contacts.

Non-local native geometries exhibit higher folding cooperativity.

Folding robustness correlates with native contact distribution.

Abstract

In protein folding the term plasticity refers to the number of alternative folding pathways encountered in response to free energy perturbations such as those induced by mutation. Here we explore the relation between folding plasticity and a gross, generic feature of the native geometry, namely, the relative number of local and non-local native contacts. The results from our study, which is based on Monte Carlo simulations of simple lattice proteins, show that folding to a structure that is rich in local contacts is considerably more plastic than folding to a native geometry characterized by having a very large number of long-range contacts (i.e., contacts between amino acids that are separated by more than 12 units of backbone distance). The smaller folding plasticity of `non-local' native geometries is probably a direct consequence of their higher folding cooperativity that renders the folding reaction more robust against single- and multiple-point mutations.