Prediction and Evaluation of Coronavirus and Human Protein–Protein Interactions Integrating Five Different Computational Methods

The high lethality and infectiousness of coronaviruses, particularly SARS-Cov-2, pose a significant threat to human society. Understanding coronaviruses, especially the interactions between these viruses and humans, is crucial for mitigating the coronavirus pandemic. In this study, we conducted a comprehensive comparison and evaluation of five prevalent computational methods: interolog mapping, domain-domain interaction methodology, domain-motif interaction methodology, structure-based approaches, and machine learning techniques. These methods were assessed using unbiased datasets that include C1, C2h, C2v, and C3 test sets. Ultimately, we integrated these five methodologies into a unified model for predicting protein-protein interactions (PPIs) between coronaviruses and human proteins. Our final model demonstrates relatively better performance, particularly with the C2v and C3 test sets, which are frequently used datasets in practical applications. Based on this model, we further established a high-confidence PPI network between coronaviruses and humans, consisting of 18,012 interactions between 3843 human proteins and 129 coronavirus proteins. The reliability of our predictions was further validated through the current knowledge framework and network analysis. This study is anticipated to enhance mechanistic understanding of the coronavirus-human relationship a while facilitating the rediscovery of antiviral drug targets. The source codes and datasets are accessible at https://github.com/covhppilab/CoVHPPI.