Abstract
AbstractThe accurate description and analysis of protein-protein interfaces remains a challenging task. Traditional definitions, based on atomic contacts or changes in solvent accessibility, tend to over- or underpredict the interface itself and cannot discriminate active from less relevant parts.We here extend a fast, parameter-free and purely geometric definition of protein interfaces and introduce the shelling order of Voronoi facets as a novel measure for an atom's depth inside the nterface. Our analysis of 54 protein-protein complexes reveals a strong correlation between Voronoi Shelling Order (VSO) and water dynamics. High Voronoi Shelling Order coincides with residues that were found shielded from bulk water fluctuations in a recent molecular dynamics study. Yet, VSO predicts such "dry" residues at dramatically reduced cost and without consideration of forcefields or dynamics. More central interface positions are often also increasingly enriched for hydrophobic residues. Yet, this hydrophobic centering is not universal and does not mirror the far stronger geometric bias of water fluxes. The seemingly complex water dynamics at protein interfaces appears thus largely controlled by geometry. Sequence analysis supports the functional relevance of both dry residues and residues with high VSO, both of which tend to be more conserved. However, upon closer inspection, the spatial distribution of conservation argues against the arbitrary dissection into core or rim and thus refines previous results. Voronoi Shelling Order reveals clear geometric patterns in protein interface composition, function and dynamics and facilitates the comparative analysis of protein-protein interactions.
Highlights
Specific recognition between proteins plays a crucial role in almost all cellular processes and most proteins are embedded in highly connected networks of interaction partners [1]
In order to characterize all possible relationships, we examine, further down in the text, how good a predictor of shelling order conservation is
The idea is related to the concept of residue or atom depth [43, 44] which shows some correlation with thermodynamic properties [43] and residue conservation [45] in globular proteins
Summary
Specific recognition between proteins plays a crucial role in almost all cellular processes and most proteins are embedded in highly connected (and dynamically changing) networks of interaction partners [1]. As contributions to specificity and affinity appeared very unevenly distributed, substantial effort has been spent on the identification of areas or residue patches that are actively involved in molecular recognition [7, 8, 9, 10] This lead to the definition of ‘hotspot’ residues [11, 12]. Hotspots refer to the usually very small number [12] of ‘key’ residues in a protein-protein interface, the mutation of which causes large changes in the binding free energy. Contrary to this focus on isolated residues, more recent studies have revealed strong non-additive, collective effects [13] which point to a modular organization of interfaces into interaction clusters [14]
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