Abstract
BackgroundThe study of protein-protein interactions is becoming increasingly important for biotechnological and therapeutic reasons. We can define two major areas therein: the structural prediction of protein-protein binding mode, and the identification of the relevant residues for the interaction (so called 'hot-spots'). These hot-spot residues have high interest since they are considered one of the possible ways of disrupting a protein-protein interaction. Unfortunately, large-scale experimental measurement of residue contribution to the binding energy, based on alanine-scanning experiments, is costly and thus data is fairly limited. Recent computational approaches for hot-spot prediction have been reported, but they usually require the structure of the complex.ResultsWe have applied here normalized interface propensity (NIP) values derived from rigid-body docking with electrostatics and desolvation scoring for the prediction of interaction hot-spots. This parameter identifies hot-spot residues on interacting proteins with predictive rates that are comparable to other existing methods (up to 80% positive predictive value), and the advantage of not requiring any prior structural knowledge of the complex.ConclusionThe NIP values derived from rigid-body docking can reliably identify a number of hot-spot residues whose contribution to the interaction arises from electrostatics and desolvation effects. Our method can propose residues to guide experiments in complexes of biological or therapeutic interest, even in cases with no available 3D structure of the complex.
Highlights
The study of protein-protein interactions is becoming increasingly important for biotechnological and therapeutic reasons
The normalized interface propensity (NIP) values derived from rigid-body docking can reliably identify a number of hotspot residues whose contribution to the interaction arises from electrostatics and desolvation effects
Residue interface propensities from rigid-body docking scored by electrostatics and desolvation We recently described the residue-based normalized interface propensity (NIP) parameter, computed from an ensemble of the 100 lowest-energy ICM docking solutions as sorted by a rigid-body docking energy function
Summary
The study of protein-protein interactions is becoming increasingly important for biotechnological and therapeutic reasons. Knowing the binding mode of two interacting proteins, or even better, the residues directly responsible for the interaction (so called 'hot-spots'), could help to the long-awaited goal of disrupting the complex with small molecules [3,4], which would open enormous biological and therapeutic expectations For this reason, hot-spot residues, typically defined as those residues contributing in more than 1 or 2 kcal.mol-1 to the total binding energy of the complex, are attractive to the pharmaceutical field. Hot-spots are surrounded by moderately conserved and energetically less important residues forming a hydrophobic O-ring responsible for bulk solvent exclusion [5,9] They appear to be clustered in tightly packed regions in the centre of the interface [8]. It has not been found any single attribute as shape, charge or hydrophobicity that can unequivocally define a hotspot by itself [3,6,10,11]
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