Abstract
We report a simple algorithm to scan interfaces in protein–protein complexes for identifying binding ‘hot spots’. The change in side-chain solvent accessible area (ΔASA) of interface residues has been related to change in binding energy due to mutating interface residues to Ala (ΔΔG X → ALA) based on two criteria—hydrogen bonding across the interface and location in the interface core—both of which are major determinants in specific, high-affinity binding. These relationships are used to predict the energetic contribution of individual interface residues. The predictions are tested against 462 experimental X → ALA mutations from 28 interfaces with an average unsigned error of 1.04 kcal/mol. More than 80% of interface hot spots (with experimental ΔΔG ≥ 2 kcal/mol) could be identified as being energetically important. From the experimental values, Asp, Lys, Tyr and Trp are found to contribute most of the binding energy, burying >45 Å2 on average. The method described here would be useful to understand and interfere with protein interactions by assessing the energetic importance of individual interface residues.
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Acknowledgments
We are grateful to Prof. Joël Janin for his comments on the manuscript. MG is a recipient of a senior research fellowship from CSIR and PC is a JC Bose National Fellow. The funding was provided by DBT, India.
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Guharoy, M., Chakrabarti, P. Empirical estimation of the energetic contribution of individual interface residues in structures of protein–protein complexes. J Comput Aided Mol Des 23, 645–654 (2009). https://doi.org/10.1007/s10822-009-9282-3
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DOI: https://doi.org/10.1007/s10822-009-9282-3