The Most Severe Test for Hydrophobicity Scales: Two Proteins with 88% Sequence Identity but Different Structure and Function

TL;DR

This paper introduces a novel approach to evaluating hydrophobicity scales in proteins by analyzing two proteins with high sequence similarity but different structures and functions, highlighting the limitations of traditional scales.

Contribution

It proposes a new method based on proteins as self-organized networks and tests it against challenging proteins, providing insights beyond classical force field approaches.

Findings

The new method confirms the validity of KD's hydrophobicity evaluation.

Protein structure prediction remains challenging due to delicate balances in protein networks.

Hydrophobicity scales can be effectively assessed without classical force fields.

Abstract

Protein-protein interactions (protein functionalities) are mediated by water, which compacts individual proteins and promotes close and temporarily stable large-area protein-protein interfaces. In their classic paper Kyte and Doolittle (KD) concluded that the "simplicity and graphic nature of hydrophobicity scales make them very useful tools for the evaluation of protein structures". In practice, however, attempts to develop hydrophobicity scales (for example, compatible with classical force fields (CFF) in calculating the energetics of protein folding) have encountered many difficulties. Here we suggest an entirely different approach, based on the idea that proteins are self-organized networks, subject to finite-scale criticality (like some network glasses). We test this proposal against two small proteins that are delicately balanced between alpha and alpha/beta structures, with different functions encoded with only 12% of their amino acids. This example explains why protein structure prediction is so challenging, and it provides a severe test for the accuracy and content of hydrophobicity scales. The new method confirms KD's evaluation, and at the same time suggests that protein structure, dynamics and function can be best discussed without using CFF.