A 3D structural SARS-CoV-2-human interactome to explore genetic and drug perturbations

Emergence of new viral agents is driven by evolution of interactions between viral proteins and host targets. For instance, increased infectivity of SARS-CoV-2 compared to SARS-CoV-1 arose in part through rapid evolution along the interface between the spike protein and its human receptor ACE2, leading to increased binding affinity. To facilitate broader exploration of how pathogen-host interactions might impact transmission and virulence in the ongoing COVID-19 pandemic, we performed state-of-the-art interface prediction followed by molecular docking to construct a three-dimensional structural interactome between SARS-CoV-2 and human. We additionally carried out downstream meta-analyses to investigate enrichment of sequence divergence between SARS-CoV-1 and SARS-CoV-2 or human population variants along viral-human protein-interaction interfaces, predict changes in binding affinity by these mutations/variants and further prioritize drug repurposing candidates predicted to competitively bind human targets. We believe this resource (http://3D-SARS2.yulab.org) will aid in development and testing of informed hypotheses for SARS-CoV-2 etiology and treatments.

Automated summary

The emergence of new viral agents is driven by evolution of interactions between viral proteins and host targets, leading to increased infectivity of viruses such as SARS-CoV-2 through rapid evolution. State-of-the-art interface prediction and molecular docking were used to construct a three-dimensional structural interactome between SARS-CoV-2 and human, facilitating the study of how pathogen-host interactions impact transmission and virulence. The resource provided aims to aid in the development and testing of informed hypotheses for understanding the etiology and treatments of SARS-CoV-2.