Probing the Origins of Two-State Folding

TL;DR

This paper introduces a minimal model explaining why many proteins fold via a two-state process, emphasizing the role of native state occupancy and providing insights consistent with experimental data.

Contribution

A new minimal model demonstrating that two-state folding emerges naturally when the native state is highly populated, explaining experimental observations.

Findings

Two-state folding is emergent and strengthened by native state occupancy.

Unfolded states equilibrate quickly despite slow interconversions.

Model aligns with experimental folding rate data.

Abstract

Many protein systems fold in a two-state manner. Random models, however, rarely display two-state kinetics and thus such behavior should not be accepted as a default. To date, many theories for the prevalence of two-state kinetics have been presented, but none sufficiently explain the breadth of experimental observations. A model, making a minimum of assumptions, is introduced that suggests two-state behavior is likely for any system with an overwhelmingly populated native state. We show two-state folding is emergent and strengthened by increasing the occupancy population of the native state. Further, the model exhibits a hub-like behavior, with slow interconversions between unfolded states. Despite this, the unfolded state equilibrates quickly relative to the folding time. This apparent paradox is readily understood through this model. Finally, our results compare favorable with experimental measurements of protein folding rates as a function of chain length and Keq, and provide new insight into these results.