title: Solvent Sites Improve Docking Performance of Protein–Protein Complexes and Protein–Protein Interface-Targeted Drugs
author: Gonzalo F. Mayol
description: Protein–protein interactions (PPIs) are essential, and modulating their function through PPI-targeted drugs is an important research field. PPI sites are shallow protein surfaces readily accessible to the solvent, thus lacking a proper pocket to fit a drug, while their lack of endogenous ligands prevents drug design by chemical similarity. The development of PPI-blocking compounds is, therefore, a tough challenge. Mixed solvent molecular dynamics has been shown to reveal protein–ligand interaction hot spots in protein active sites by identifying solvent sites (SSs). Furthermore, our group has shown that SSs significantly improve protein–ligand docking. In the present work, we extend our analysis to PPI sites. In particular, we analyzed water, ethanol, and phenol-derived sites in terms of their capacity to predict protein–drug and protein–protein interactions. Subsequently, we show how this information can be incorporated to improve both protein–ligand and protein–protein docking. Finally, we highlight the presence of aromatic clusters as key elements of the corresponding interactions.