Theoretical Perspectives on Protein Folding

TL;DR

This paper reviews theoretical and experimental advances in understanding protein folding mechanisms, emphasizing universal features, the influence of protein size, and the integration of models with single-molecule experiments.

Contribution

It introduces the Molecular Transfer Model combining simulations with transfer free energies to predict folding details based on protein topology and size.

Findings

Protein size influences folding transition cooperativity

Single-molecule methods validate N-dependent folding heterogeneity

The Molecular Transfer Model predicts folding pathways and timescales

Abstract

Understanding how monomeric proteins fold under in vitro conditions is crucial to describing their functions in the cellular context. Significant advances both in theory and experiments have resulted in a conceptual framework for describing the folding mechanisms of globular proteins. The experimental data and theoretical methods have revealed the multifaceted character of proteins. Proteins exhibit universal features that can be determined using only the number of amino acid residues (N) and polymer concepts. The sizes of proteins in the denatured and folded states, cooperativity of the folding transition, dispersions in the melting temperatures at the residue level, and time scales of folding are to a large extent determined by N. The consequences of finite N especially on how individual residues order upon folding depends on the topology of the folded states. Such intricate details can be predicted using the Molecular Transfer Model that combines simulations with measured transfer free energies of protein building blocks from water to the desired concentration of the denaturant. By watching one molecule fold at a time, using single molecule methods, the validity of the theoretically anticipated heterogeneity in the folding routes, and the N-dependent time scales for the three stages in the approach to the native state have been established. Despite the successes of theory, of which only a few examples are documented here, we conclude that much remains to be done to solve the "protein folding problem" in the broadest sense.