Finding a unifying motif of intermolecular cooperativity in protein associations

TL;DR

This paper identifies a unifying molecular motif in protein-protein interfaces, where hot spots contribute to intermolecular cooperativity through electrostatic interactions, aiding in drug design.

Contribution

It reveals a common electrostatic wrapping motif in hot spots that underpins intermolecular cooperativity in protein associations, offering new insights for therapeutic targeting.

Findings

Hot spots share a unifying electrostatic motif.

This motif is crucial for interface integrity.

Potential for designing molecules to disrupt protein interactions.

Abstract

At the molecular level, most biological processes entail protein associations which in turn rely on a small fraction of interfacial residues called hot spots. Here we show that hot spots share a unifying molecular attribute: they provide a third-body contribution to intermolecular cooperativity. Such motif, based on the wrapping of interfacial electrostatic interactions, is essential to maintain the integrity of the interface and can be exploited in rational drug design since such regions may serve as blueprints to engineer small molecules disruptive of protein-protein interfaces.