Quantitative Characterization of the Impact of Protein–Protein Interactions on Ligand–Protein Binding: A Multi-Chain Dynamics Perturbation Analysis Method

Many protein–protein interactions (PPIs) affect the ways in which small molecules bind to their constituent proteins, which can impact drug efficacy and regulatory mechanisms. While recent advances have improved our ability to independently predict both PPIs and ligand–protein interactions (LPIs), a comprehensive understanding of how PPIs affect LPIs is still lacking. Here, we examined 63 pairs of ligand–protein complexes in a benchmark dataset for protein–protein docking studies and quantified six typical effects of PPIs on LPIs. A multi-chain dynamics perturbation analysis method, called mcDPA, was developed to model these effects and used to predict small-molecule binding regions in protein–protein complexes. Our results illustrated that the mcDPA can capture the impact of PPI on LPI to varying degrees, with six similar changes in its predicted ligand-binding region. The calculations showed that 52% of the examined complexes had prediction accuracy at or above 50%, and 55% of the predictions had a recall of not less than 50%. When applied to 33 FDA-approved protein–protein-complex-targeting drugs, these numbers improved to 60% and 57% for the same accuracy and recall rates, respectively. The method developed in this study may help to design drug–target interactions in complex environments, such as in the case of protein–protein interactions.