Abstract
AbstractProtein-protein interactions (PPIs) govern virtually all cellular processes. Even a single mutation within PPI can significantly influence overall protein functionality and potentially lead to various types of diseases. To date, numerous approaches have emerged for predicting the change in free energy of binding (ΔΔGbind) resulting from mutations, yet the majority of these methods lack precision. In recent years, protein language models (PLMs) have been developed and shown powerful predictive capabilities by leveraging both sequence and structural data from protein-protein complexes. Yet, PLMs have not been optimized specifically for predicting ΔΔGbind. We developed an approach to predict effects of mutations on PPI binding affinity based on two most advanced protein language models ESM2 and ESM-IF1 that incorporate PPI sequence and structural features, respectively. We used the two models to generate embeddings for each PPI mutant and subsequently fine-tuned our model by training on a large dataset of experimental ΔΔGbindvalues. Our model, ProBASS (Protein Binding Affinity from Structure and Sequence) achieved a correlation with experimental ΔΔGbindvalues of 0.83 ± 0.05 for single mutations and 0.69 ± 0.04 for double mutations when model training and testing was done on the same PDB. Moreover, ProBASS exhibited very high correlation (0.81 ± 0.02) between prediction and experiment when training and testing was performed on a dataset containing 2325 single mutations in 132 PPIs. ProBASS surpasses the state-of-the-art methods in correlation with experimental data and could be further trained as more experimental data becomes available. Our results demonstrate that the integration of extensive datasets containing ΔΔGbindvalues across multiple PPIs to refine the pre-trained PLMs represents a successful approach for achieving a precise and broadly applicable model for ΔΔGbindprediction, greatly facilitating future protein engineering and design studies.
Publisher
Cold Spring Harbor Laboratory