Folding and Misfolding of Designed Heteropolymer Chains with Mutations

TL;DR

This study investigates how mutations influence the folding and misfolding of designed heteropolymer chains, highlighting the roles of different mutation types on folding dynamics and stability.

Contribution

It demonstrates the differential impact of mutations on folding times and stability, emphasizing the significance of the energy gap in protein-like heteropolymer folding.

Findings

Half to one third of mutations ('cold errors') slow folding but still allow native structure formation.

A small number of mutations ('hot errors') cause significant misfolding.

Mutations mainly alter the native state's energetics, supporting the energy gap concept.

Abstract

We study the impact of mutations (changes in amino acid sequence) on the thermodynamics of simple protein-like heteropolymers consisting of N monomers, representing the amino acid sequence. The sequence is designed to fold into its native conformation on a cubic lattice. It is found that quite a large fraction, between one half and one third of the substitutions, which we call 'cold errors', make important contributions to the dynamics of the folding process, increasing folding times typically by a factor of two, the altered chain still folding into the native structure. Few mutations ('hot errors'), have quite dramatic effects, leading to protein misfolding. Our analysis reveals that mutations affect primarily the energetics of the native conformation and to a much lesser extent the ensemble of unfolded conformations, corroborating the utility of the ``energy gap'' concept for the analysis of folding properties of protein-like heteropolymers.