Learning the protein language of proteome-wide protein-protein binding sites via explainable ensemble deep learning

Protein-protein interactions (PPIs) govern cellular pathways and processes, by significantly influencing the functional expression of proteins. Therefore, accurate identification of protein-protein interaction binding sites has become a key step in the functional analysis of proteins. However, since most computational methods are designed based on biological features, there are no available protein language models to directly encode amino acid sequences into distributed vector representations to model their characteristics for protein protein binding events. Moreover, the number of experimentally detected protein interaction sites is much smaller than that of protein-protein interactions or protein sites in protein complexes, resulting in unbalanced data sets that leave room for improvement in their performance. To address these problems, we develop an ensemble deep learning model (EDLM)-based protein-protein interaction (PPI) site identification method (EDLMPPI). Evaluation results show that EDLMPPI outperforms state-of-the-art techniques including several PPI site prediction models on three widely-used benchmark datasets including Dset_448, Dset_72, and Dset_164, which demonstrated that EDLMPPI is superior to those PPI site prediction models by nearly 10% in terms of average precision. In addition, the biological and interpretable analyses provide new insights into protein binding site identification and characterization mechanisms from different perspectives. The EDLMPPI webserver is available at http://www.edlmppi.top:5002/.

Automated summary

Protein-protein interactions (PPIs) play a crucial role in cellular pathways and processes, but accurate identification of PPI binding sites is challenging. The proposed EDLM-based method, EDLMPPI, addresses these challenges by utilizing an ensemble deep learning model. Evaluation results demonstrate that EDLMPPI outperforms state-of-the-art techniques in terms of average precision on widely-used benchmark datasets. Additionally, the method provides new insights into protein binding site identification and characterization mechanisms.