Abstract:
In this study, we mined the PDB and created a structural library of 178,465 interfaces that mediate protein–protein/domain–domain interactions. Interfaces involving the same CATH fold(s) were clustered together. Our analysis of the library reveals similarities between chain–chain and domain–domain interactions. The library also illustrates how a single protein fold can interact with multiple folds using similar interfaces. The library is hence a useful resource to study the types of interactions between protein folds. Analyzing the data in the library reveals various interesting aspects of protein–protein and domain–domain interactions such as how proteins belonging to folds that interact with many other folds also have high number of Enzyme Commission terms. These data could be utilized to seek potential binding partners. It can also be utilized to investigate the different ways in which two or more folds interact with one another structurally. We constructed a statistical potential of pair preferences of amino acids across the interface for chain–chain and domain–domain interactions separately. They are quite similar further lending credence to the notion that domain–domain interfaces could be used to study chain–chain interactions. We analyzed protein complexes modeled by AlphaFold2 and RoseTTAFold and noticed that some of the modes of interaction involve folds and interfaces that have not been observed to bind in the PDB. Lastly and importantly, the library includes predicted small molecule-binding sites at protein–protein interfaces. This has applications as interfaces containing small molecule-binding sites can be easily targeted to prevent the interaction and perhaps form a part of a therapeutic strategy.