Structure-based prediction of protein-folding transition paths

TL;DR

This paper introduces a theoretical framework for predicting protein-folding transition paths, highlighting the role of transient states and critical contacts, and providing insights into folding mechanisms and rate-limiting steps.

Contribution

It presents a novel, general theory linking native structure to folding pathways and transition states, advancing understanding of protein self-assembly and folding kinetics.

Findings

Transition paths involve high-free-energy transient states separated by barriers.

Critical contacts between substructures determine the transition state.

The theory predicts the rate-limiting step in folding reactions.

Abstract

We propose a general theory to describe the distribution of protein-folding transition paths. We show that transition paths follow a predictable sequence of high-free-energy transient states that are separated by free-energy barriers. Each transient state corresponds to the assembly of one or more discrete, cooperative units, which are determined directly from the native structure. We show that the transition state on a folding pathway is reached when a small number of critical contacts are formed between a specific set of substructures, after which folding proceeds downhill in free energy. This approach suggests a natural resolution for distinguishing parallel folding pathways and provides a simple means to predict the rate-limiting step in a folding reaction. Our theory identifies a common folding mechanism for proteins with diverse native structures and establishes general principles for the self-assembly of polymers with specific interactions.