A unifying motif of intermolecular cooperativity in protein associations

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. Our theoretical analysis shows 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. Thus, our main result is to unravel the molecular nature of the protein association problem by revealing its underlying physics and thus by casting it in simple physical grounds. Such knowledge could then be exploited in rational drug design since the regions here indicated may serve as blueprints to engineer small molecules disruptive of protein-protein interfaces.

Productive induced metastability in allosteric modulation of kinase function

“…Thus, this application illustrates that intramolecular hydrogen bonds are not only determinants of protein structure, but also promoters of protein association and functional modualtion. At variance with previous work on dehydron physics , the allosteric dehydrons described here are dynamically induced through allosteric conformational change and not are pre‐existent.…”

“…To prevail in water environments, soluble proteins protect their backbone hydrogen bonds (hydrogen bonds) from the disruptive effect of water attack by clustering nonpolar residues around them. This exclusion of the surrounding water, or wrapping effect , also enhances the electrostatic contribution by modulating the local dielectric (descreening the partial charges) and thus stabilizes the hydrogen bond. In turn, and as demonstrated previously, underwrapped interactions represent packing defects, the so‐called dehydrons, where the surrounding water has not been properly excluded; being thus adhesive, dehydrons promote protein associations because their inherent stability increases upon the approach of additional nonpolar residues .…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…To prevail in water environments, soluble proteins must protect their backbone hydrogen bonds from the disruptive effect of water attack by clustering nonpolar residues around them [252][253][254][255][256][257][258][259][260]. This exclusion of surrounding water, or wrapping effect, also enhances the electrostatic contribution by modulating the local dielectric (descreening the partial charges) and thus stabilizes the HB.…”

“…Thus, dehydrons constitute key motifs that signal protein binding sites. Under this scenario, the integrity of the interface of a biomolecular complex (when a protein binds to another protein or to a small-molecule ligand) becomes extremely reliant on intermolecular cooperativity based on three-body correlations [252][253][254][255][256][257][258][259][260]: a third nonpolar body protects an electrostatic interaction pairing the other two and not all three bodies belong to the same molecule. Thus, wrapper (nonpolar) groups become relevant for binding interactions when an interfacial hydrogen bond relies on them in order to remain over a critical wrapping value essential on stability terms.…”

“…Thus, wrapper (nonpolar) groups become relevant for binding interactions when an interfacial hydrogen bond relies on them in order to remain over a critical wrapping value essential on stability terms. Such a decomposition of the complex interface into a web of three-body cooperative interactions enabled us to successfully predict the hot spots reported by alanine-scanning experimental studies for a set of protein-protein complexes [259].…”