Stretching Single Domain Proteins: Phase Diagram and Kinetics of Force-Induced Unfolding

TL;DR

This paper develops a theoretical framework using lattice models to analyze force-induced unfolding of single domain proteins, revealing cooperative and intermediate pathways, heterogeneity in unfolding rates, and the potential to map folding landscapes.

Contribution

It introduces a novel lattice model approach to predict phase diagrams and kinetics of force-induced protein unfolding, aligning with experimental observations.

Findings

Two-state folders unravel cooperatively at zero force

Unfolding involves intermediates in non-two-state folders

Unfolding rates increase exponentially with force until an optimal point

Abstract

Single molecule force spectroscopy reveals unfolding of domains in titin upon stretching. We provide a theoretical framework for these experiments by computing the phase diagrams for force-induced unfolding of single domain proteins using lattice models. The results show that two-state folders (at zero force) unravel cooperatively whereas stretching of non-two-state folders occurs through intermediates. The stretching rates of individual molecules show great variations reflecting the heterogeneity of force-induced unfolding pathways. The approach to the stretched state occurs in a step-wise "quantized" manner. Unfolding dynamics depends sensitively on topology. The unfolding rates increase exponentially with force f till an optimum value which is determined by the barrier to unfolding when f=0. A mapping of these results to proteins shows qualitative agreement with force-induced unfolding of Ig-like domains in titin. We show that single molecule force spectroscopy can be used to map the folding free energy landscape of proteins in the absence of denaturants.