Local Geometry and Evolutionary Conservation of Protein Surfaces Reveal the Multiple Recognition Patches in Protein-Protein Interactions.

Elodie Laine,Alessandra Carbone,Nir Ben-Tal

doi:10.1371/journal.pcbi.1004580

Abstract

Protein-protein interactions (PPIs) are essential to all biological processes and they represent increasingly important therapeutic targets. Here, we present a new method for accurately predicting protein-protein interfaces, understanding their properties, origins and binding to multiple partners. Contrary to machine learning approaches, our method combines in a rational and very straightforward way three sequence- and structure-based descriptors of protein residues: evolutionary conservation, physico-chemical properties and local geometry. The implemented strategy yields very precise predictions for a wide range of protein-protein interfaces and discriminates them from small-molecule binding sites. Beyond its predictive power, the approach permits to dissect interaction surfaces and unravel their complexity. We show how the analysis of the predicted patches can foster new strategies for PPIs modulation and interaction surface redesign. The approach is implemented in JET2, an automated tool based on the Joint Evolutionary Trees (JET) method for sequence-based protein interface prediction. JET2 is freely available at www.lcqb.upmc.fr/JET2.

Highlights

Proteins regulate biological processes through a complex network of dynamical interactions
One would like to estimate the number of interactions for a protein, identify precisely the borders of each interaction site possibly overlapping other sites, understand the structure and the usage of a moonlighting protein interaction site shared with several partners, identify the anchor points in an interaction site that allow for strong versus weak binding, identify the locations on a protein surface where artificial molecules could best interfere with protein partners
Protein interfaces are comprised of residues issued by a combination of conservation and/or physico-chemical properties and extend through neighboring protruding regions. We propose this three-layer structure to be characteristic of protein-protein interfaces and, based on it, we provide a large-scale predictive pipeline, called JET2

Summary

Introduction

Proteins regulate biological processes through a complex network of dynamical interactions. The amino acids forming the interface core tend to be more hydrophobic than over the rim [14,15,16,17]; they are more frequently hotspots [18] and, usually more conserved [19,20,21,22,23]. Starting from these observations, a formal structural definition of these regions was proposed and a new structural region, the support, was introduced [24]. An effort was engaged to define multiple recognition patches in large protein interfaces [25]

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Conclusion