Predicting mutational effects on protein-protein binding via a side-chain diffusion probabilistic model
This work addresses a key problem in protein engineering and therapeutic discovery by improving prediction accuracy for mutational effects on binding.
The authors tackled the problem of predicting mutational effects on protein-protein binding, which is challenging due to scarce annotated data, by proposing SidechainDiff, a diffusion model for side-chain conformations, and achieved state-of-the-art performance.
Many crucial biological processes rely on networks of protein-protein interactions. Predicting the effect of amino acid mutations on protein-protein binding is vital in protein engineering and therapeutic discovery. However, the scarcity of annotated experimental data on binding energy poses a significant challenge for developing computational approaches, particularly deep learning-based methods. In this work, we propose SidechainDiff, a representation learning-based approach that leverages unlabelled experimental protein structures. SidechainDiff utilizes a Riemannian diffusion model to learn the generative process of side-chain conformations and can also give the structural context representations of mutations on the protein-protein interface. Leveraging the learned representations, we achieve state-of-the-art performance in predicting the mutational effects on protein-protein binding. Furthermore, SidechainDiff is the first diffusion-based generative model for side-chains, distinguishing it from prior efforts that have predominantly focused on generating protein backbone structures.