Optimal docking area: A new method for predicting protein–protein interaction sites

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Abstract
Understanding energetics and mechanism of protein–protein association remains one of the biggest theoretical problems in structural biology. It is assumed that desolvation must play an essential role during the association process, and indeed protein–protein interfaces in obligate complexes have been found to be highly hydrophobic. However, the identification of protein interaction sites from surface analysis of proteins involved in non‐obligate protein–protein complexes is more challenging. Here we present Optimal Docking Area (ODA), a new fast and accurate method of analyzing a protein surface in search of areas with favorable energy change when buried upon protein–protein association. The method identifies continuous surface patches with optimal docking desolvation energy based on atomic solvation parameters adjusted for protein–protein docking. The procedure has been validated on the unbound structures of a total of 66 non‐homologous proteins involved in non‐obligate protein–protein hetero‐complexes of known structure. Optimal docking areas with significant low‐docking surface energy were found in around half of the proteins. The ‘ODA hot spots’ detected in X‐ray unbound structures were correctly located in the known protein–protein binding sites in 80% of the cases. The role of these low‐surface‐energy areas during complex formation is discussed. Burial of these regions during protein–protein association may favor the complexed configurations with near‐native interfaces but otherwise arbitrary orientations, thus driving the formation of an encounter complex. The patch prediction procedure is freely accessible at http://www.molsoft.com/oda and can be easily scaled up for predictions in structural proteomics. Proteins 2005.