Assessment of hydrophobicity scales for protein stability and folding using energy and RMSD criteria

TL;DR

This study systematically evaluates various hydrophobicity scales in protein folding simulations, tuning them for better native structure preservation and comparing their predictive accuracy using energy and RMSD metrics.

Contribution

It introduces a quantitative assessment method for hydrophobicity scales in protein folding, including tuning scales and using ER-score for comparison.

Findings

Hydrophobicity scales vary significantly in their ability to predict native structures.

Tuning hydrophobicity scales improves folding accuracy.

ER-score effectively compares the predictive performance of different scales.

Abstract

De novo prediction of protein folding is an open scientific challenge. Many folding models and force fields have been developed, yet all face difficulties converging to native conformations. Hydrophobicity scales (HSs) play a crucial role in such simulations as they define the energetic interactions between protein residues, thus determining the energetically favorable conformation. While many HSs have been developed over the years using various methods, it is surprising that the scales show very weak consensus in their assignment of hydrophobicity indexes to the various residues. In this work, several HSs are systematically assessed via atomistic Monte Carlo simulation of folding of small proteins, by converting the HSs of interest into residue-residue contact energy matrices. HSs that poorly preserve native structures of proteins were tuned by applying a linear transformation. Subsequently, folding simulations were used to examine the ability of the HSs to correctly fold the proteins from a random initial conformation. Root mean square deviation (RMSD) and energy of the proteins during folding were sampled and used to define an ER-score, as the correlation between the 2-dimensional energy-RMSD (ER) histogram with 50% lowest energy conformations and the ER histogram with 50% lowest RMSD conformations. Thus, we were able to compare the ability of the different HSs to predict de novo protein folding quantitatively.