Exploring the mechanisms of protein folding

TL;DR

This paper challenges traditional theories of protein folding by proposing a meso-science perspective that emphasizes the dynamic interplay between free energy and environmental factors, supported by simulation data.

Contribution

It introduces a novel meso-scale, dissipative, nonlinear, non-equilibrium framework for understanding protein folding, highlighting the importance of multiple mechanisms and dynamic characteristic states.

Findings

Protein folding involves dynamic characteristic states beyond minimum free energy.

Simulations show the coexistence of multiple mechanisms influencing folding.

Understanding multiple mechanisms is key to grasping protein folding complexity.

Abstract

Neither of the two prevalent theories, namely thermodynamic stability and kinetic stability, provides a comprehensive understanding of protein folding. The thermodynamic theory is misleading because it assumes that free energy is the exclusive dominant mechanism of protein folding, and attributes the structural transition from one characteristic state to another to energy barriers. Conversely, the concept of kinetic stability overemphasizes dominant mechanisms that are related to kinetic factors. This article explores the stability condition of protein structures from the viewpoint of meso-science, paying attention to the compromise in the competition between minimum free energy and other dominant mechanisms. Based on our study of complex systems, we propose that protein folding is a meso-scale, dissipative, nonlinear and non-equilibrium process that is dominated by the compromise between free energy and other dominant mechanisms such as environmental factors. Consequently, a protein shows dynamic structures, featuring characteristic states that appear alternately and dynamically, only one of which is the state with minimum free energy. To provide evidence for this concept, we analyzed the time series of energetic and structural changes of three simulations of protein folding/unfolding. Our results indicate that thorough consideration of the multiple dynamic characteristic structures generated by multiple mechanisms may be the key to understanding protein folding.