HPInet: Interpretable prediction of Host-Pathogen protein-protein Interactions using a transformer-based neural network

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Abstract Gram-negative bacteria utilize a series of secretion systems (T1SS-T10SS) to deliver secreted effector proteins (T1SE-T10SE) into host cells, leading to infections and diseases. Understanding the interactions between these effector proteins and host proteins is crucial for unraveling the pathogenic mechanisms of bacterial pathogens. Despite advancements in sequencing technologies that have significantly enhanced our knowledge of effector protein diversity and structure, the molecular mechanisms underlying their interactions with human host proteins remain unclear. Experimental approaches to validate these interactions are labor-intensive, time-consuming, and insufficient to comprehensively map the extensive effector-host protein interaction (PPI) network. Additionally, specialized computational tools for predicting these interactions remain scarce. To address this gap, we developed HPInet, a transformer-based deep learning model for predicting interactions between bacterial effector proteins and human host proteins. HPInet introduces convolutional layers and global response normalization (GRN) into the feed-forward network (FFN) of the transformer architecture, enhancing the extraction of local sequence features. Compared to existing state-of-the-art methods, HPInet significantly improves prediction performance, increasing accuracy from 0.502 to 0.891 and boosting sensitivity by 35.3%. Furthermore, by leveraging the model’s attention mechanism, HPInet identifies critical residues at interaction sites, demonstrating its capability to capture local structural features of PPI sites solely from sequence information. To facilitate its application in research, HPInet has been implemented as a freely accessible web server available at https://bis.zju.edu.cn/hpinet . This platform provides a powerful and interpretable tool for studying effector-host protein interactions, offering valuable insights into bacterial pathogenesis and potential therapeutic targets.

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