Low energy pathways for reproducible in vivo protein folding

TL;DR

This study uses targeted molecular dynamics to explore protein folding pathways, revealing that initial alpha-helical conformations generally lead to lower energy routes to native states and highlighting the importance of intermediate structures.

Contribution

It demonstrates the effectiveness of targeted molecular dynamics in identifying low energy folding pathways and introduces the significance of intermediate structures in improving folding success rates.

Findings

Alpha-helical initial conformations yield lower energy folding pathways.

Introducing intermediate structures increases successful folding to 85%.

Targeted molecular dynamics effectively models protein folding pathways.

Abstract

Two proteins, one belonging to the mainly alpha class and the other belonging to the alpha/beta class, are selected to test a kinetic mechanism for protein folding. Targeted molecular dynamics is applied to generate folding pathways for those two proteins, starting from two well defined initial conformations: a fully extended and a alpha-helical conformation. The results show that for both proteins the alpha-helical initial conformation provides overall lower energy pathways to the native state. For the alpha/beta protein, 30 % (40%) of the pathways from an initial alpha-helix (fully extended) structure lead to unentangled native folds, a success rate that can be increased to 85 % by the introduction of a well-defined intermediate structure. These results open up a new direction in which to look for a solution to the protein folding problem, as detailed at the end.