Understanding the determinants of stability and folding of small globular proteins from their energetics

TL;DR

This paper uses molecular dynamics simulations and eigenvalue analysis to identify key 'hot' sites that determine the stability and folding speed of small globular proteins, validated by mutagenesis experiments.

Contribution

It introduces a method combining full-atom molecular dynamics and eigenvalue decomposition to pinpoint critical sites influencing protein stability and folding.

Findings

Identification of 'hot' sites controlling stability and folding

Excellent agreement with mutagenesis experimental results

Energetic maps predict folding kinetics accurately

Abstract

The results of minimal model calculations suggest that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few "hot" sites. By mean of molecular dynamics simulations around the native conformation, which simulate the protein and the surrounding solvent at full--atom level, we generate an energetic map of the equilibrium state of the protein and simplify it with an Eigenvalue decomposition. The components of the Eigenvector associated with the lowest Eigenvalue indicate which are the "hot" sites responsible for the stability and for the fast folding of the protein. Comparison of these predictions with the results of mutatgenesis experiments, performed for five small proteins, provide an excellent agreement.