Single-domain protein folding: a multi-faceted problem

TL;DR

This paper reviews recent theoretical, experimental, and simulation approaches to understanding the folding mechanisms of single-domain proteins, highlighting debates and the utility of simplified models.

Contribution

It provides a comprehensive overview of current methods and discusses how on-lattice models can clarify controversial aspects of protein folding.

Findings

Single-molecule techniques reveal complex folding pathways.

On-lattice models help resolve debates on denatured states.

Experimental results show conflicting views on folding intermediates.

Abstract

We review theoretical approaches, experiments and numerical simulations that have been recently proposed to investigate the folding problem in single-domain proteins. From a theoretical point of view, we emphasize the energy landscape approach. As far as experiments are concerned, we focus on the recent development of single-molecule techniques. In particular, we compare the results obtained with two main techniques: single protein force measurements with optical tweezers and single-molecule fluorescence in studies on the same protein (RNase H). This allows us to point out some controversial issues such as the nature of the denatured and intermediate states and possible folding pathways. After reviewing the various numerical simulation techniques, we show that on-lattice protein-like models can help to understand many controversial issues.