Molecular modelling predicts SARS-CoV-2 ORF8 protein and human complement Factor 1 catalytic domain sharing common binding site on complement C3b

Function of Open Reading Frame 8 (ORF8) protein of SARS-CoV-2 is still unclear. Here, we predict the functional role of ORF8 of SARS-CoV-2 in the context of host-pathogen relationship and the impact of mutations acquired during transmission. Mutational entropy analysis of 1042 ORF8 sequences of SARS-CoV-2 reveals a remarkable conservation among all isolates with high propensity of mutations only at amino-acid positions S24, V62, and L84. Search for structural homolog of ORF8 protein identified human complement factor 1 (F1; PDB ID: 2XRC) with 48% similarity to the C-terminus serine-protease domain. Comparative protein-protein interaction modelling predicts ORF8 binding with human complement C3b, an endogenous substrate of F1. ORF8 appears to bind via overlapping F1-interacting region on C3b (Chain B) with higher binding energy than F1-C3b complex. However, introduction of natural mutations on ORF8 reduced the binding energy. Thus, ORF8 can potentially disrupt complement activation by competing with F1 for C3b binding.