Encoding the space of protein-protein binding interfaces by artificial intelligence

The physical interactions between proteins are largely determined by the structural properties at their binding interfaces. It was found that the binding interfaces in distinctive protein complexes are highly similar. The structural properties underlying different binding interfaces could be further captured by artificial intelligence. In order to test this hypothesis, we broke protein-protein binding interfaces into pairs of interacting fragments. We employed a generative model to encode these interface fragment pairs in a low-dimensional latent space. After training, new conformations of interface fragment pairs were generated. We found that, by only using a small number of interface fragment pairs that were generated by artificial intelligence, we were able to guide the assembly of protein complexes into their native conformations. These results demonstrate that the conformational space of fragment pairs at protein-protein binding interfaces is highly degenerate. Features in this degenerate space can be well characterized by artificial intelligence. In summary, our machine learning method will be potentially useful to search for and predict the conformations of unknown protein-protein interactions.