Importance of Metastable States in the Free Energy Landscapes of Polypeptide Chains

TL;DR

This paper demonstrates that the free energy landscapes of polypeptide chains feature a limited number of metastable states linked to protein structures, with stability peaking near the folding midpoint, influencing aggregation tendencies.

Contribution

It introduces a tube-like model showing how metastable states arise from physical interactions and their relevance to protein folding and aggregation.

Findings

Metastable minima correspond to common protein motifs

Landscape complexity grows modestly with chain length

Stability peaks near the folding midpoint

Abstract

We show that the interplay between excluded volume effects, hydrophobicity, and hydrogen bonding of a tube-like representation of a polypeptide chain gives rise to free energy landscapes that exhibit a small number of metastable minima corresponding to common structural motifs observed in proteins. The complexity of the landscape increases only moderately with the length of the chain. Analysis of the temperature dependence of these landscapes reveals that the stability of specific metastable states is maximal at a temperature close to the mid-point of folding. These mestastable states are therefore likely to be of particular significance in determining the generic tendency of proteins to aggregate into potentially pathogenic agents.