Reliable protein folding on non-funneled energy landscapes: the free energy reaction path

TL;DR

This paper presents a theoretical framework for understanding protein folding dynamics on non-funneled energy landscapes, emphasizing the role of external parameter adjustment rates in achieving reliable folding.

Contribution

It introduces a new theory predicting reliable protein folding on non-funneled landscapes based on the rate of external parameter changes, supported by numerical simulations.

Findings

Reliable folding occurs when the rate r is below a calculable limit.

Folding can be reliable in both equilibrium and out-of-equilibrium conditions.

The theory is validated through simulations of model proteins.

Abstract

A theoretical framework is developed to study the dynamics of protein folding. The key insight is that the search for the native protein conformation is influenced by the rate r at which external parameters, such as temperature, chemical denaturant or pH, are adjusted to induce folding. A theory based on this insight predicts that (1) proteins with non-funneled energy landscapes can fold reliably to their native state, (2) reliable folding can occur as an equilibrium or out-of-equilibrium process, and (3) reliable folding only occurs when the rate r is below a limiting value, which can be calculated from measurements of the free energy. We test these predictions against numerical simulations of model proteins with a single energy scale.