Topological and energetic factors: what determines the structural details of the transition state ensemble and "on-route" intermediates for protein folding? An investigation for small globular proteins

TL;DR

This study demonstrates that for small globular proteins, native topology predominantly influences the structure of transition states and intermediates during folding, as shown by simplified models aligning with experimental data.

Contribution

The paper introduces simplified Go-like models that effectively replicate experimental folding transition states and intermediates, emphasizing topology's role in minimally frustrated proteins.

Findings

Models reproduce experimental transition state features

Topology is central in minimally frustrated proteins

Energetic frustration reduction aligns models with experiments

Abstract

Recent experimental results suggest that the native fold, or topology, plays a primary role in determining the structure of the transition state ensemble, at least for small fast folding proteins. To investigate the extent of the topological control of the folding process, we study the folding of simplified models of five small globular proteins constructed using a Go-like potential in order to retain the information about the native structures but drastically reduce the energetic frustration and energetic heterogeneity among residue-residue native interactions. By comparing the structure of the transition state ensemble experimentally determined by Phi-values and of the intermediates with the ones obtained using our models, we show that these energetically unfrustrated models can reproduce the global experimentally known features of the transition state ensembles and "on-route" intermediates, at least for the analyzed proteins. This result clearly indicates that, as long as the protein sequence is sufficiently minimally frustrated, topology plays a central role in determining the folding mechanism.