Coexistence of native and denatured phases in a single protein-like molecule

TL;DR

This paper investigates phase segregation in a single heteropolymer chain during protein folding and unfolding, revealing unique nucleation processes and topological constraints affecting folding kinetics.

Contribution

It introduces a computational model showing how native-like nuclei form and hinder folding, highlighting differences from vapor-liquid systems and deriving unfolding time scaling.

Findings

Native-like nuclei can hinder folding due to topological constraints.

Unfolding time scales exponentially with chain size, as exp(c N^{2/3}).

Nucleation involves a nucleus of monomers comparable to the entire chain.

Abstract

In order to understand the nuclei which develop during the course of protein folding and unfolding, we examine phase segregation of a single heteropolymer chain which occurs in equilibrium. These segregated conformations are characterized by a nucleus of monomers which are superimposable upon the native conformation. We computationally generate the phase segregation by applying a ``folding pressure,'' or adding an energetic bonus for native monomer-monomer contacts. The computer models reveal a fundamental difference in the nucleation process between heteropolymeric and the more familiar vapor-liquid systems: in a polymer system, some nuclei hinder folding via topological constraints and must be partially destroyed in order for folding to proceed. To illustrate this finding, we examine the kinetics of protein unfolding in the long chain limit through scaling arguments. We find that because of the topological constraints, the critical nucleus size is of the order of the entire chain size so that unfolding time scales as $\exp [c N^{2/3} ]$, where $N$ and $c$ are the chain length and a constant.