Investigating the side-chain structural organization behind the stability of protein folding and binding

TL;DR

This study explores the molecular features influencing protein stability and binding affinity, revealing specific amino acid roles and interaction energy contributions that underpin these processes.

Contribution

It provides a comparative analysis of amino acid composition and interaction energies related to protein folding and binding, highlighting distinct molecular mechanisms.

Findings

Hydrophobic residues are enriched in binding regions.

Charged residues are less common in binding sites.

Distant Coulombic interactions influence thermal stability.

Abstract

What are the molecular mechanisms that dictate protein-protein binding stability and whether those are related to the ones behind protein fold stability are still largely open questions. Indeed, despite many past efforts, we still lack definitive models to account for experimental quantities like protein melting temperature or complex binding affinity. Here, we investigate and compare chemical and physical features on a dataset of protein with known melting temperature as well as a large dataset of protein-protein complexes with reliable experimental binding affinity. In particular, we probed the aminoacid composition and the organization of the network of intramolecular and intermolecular interaction energies among residues. We found that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. In addition, the abundance of polar amino acid like Serine and Proline correlates with the binding affinity of the complexes. Analysing the interaction energies we found that distant Coulombic interactions are responsible for thermal stability while the total inter-molecular van der Waals energy correlates with protein-protein binding affinity.