Aromatic clusters in protein\u2013protein and protein\u2013drug complexes

Abstract

Aromatic rings are important residues for biological interactions and appear to a large extent as part of protein–drug and protein–protein interactions. They are relevant for both protein stability and molecular recognition processes due to their natural occurrence in aromatic aminoacids (Trp, Phe, Tyr and His) as well as in designed drugs since they are believed to contribute to optimizing both affinity and specificity of drug-like molecules. Despite the mentioned relevance, the impact of aromatic clusters on protein–protein and protein–drug complexes is still poorly characterized, especially in those that go beyond a dimer. In this work, we studied protein–drug and protein–protein complexes and systematically analyzed the presence and structure of their aromatic clusters. Our results show that aromatic clusters are highly prevalent in both protein–protein and protein–drug complexes, and suggest that protein–protein aromatic clusters have idealized interactions, probably because they were optimized by evolution, as compared to protein–drug clusters that were manually designed. Interestingly, the configuration, solvent accessibility and secondary structure of aromatic residues in protein–drug complexes shed light on the relation between these properties and compound affinity, allowing researchers to better design new molecules.