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bioRxiv · 10.1101/2020.06.08.107011

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

Singh, J.·Kar, S.·Ganguly, S.·Hasnain, S. E.
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Abstract

Pathogens are often known to use host factor mimicry to take evolutionary advantage. As the function of the non-structural ORF8 protein of SARS-CoV-2 in the context of host-pathogen relationship is still obscure, we investigated its role in host factor mimicry using computational protein modelling techniques. Modest sequence similarity of ORF8 of SARS-CoV-2 with the substrate binding site within the C-terminus serine-protease catalytic domain of human complement factor 1 (F1; PDB ID: 2XRC), prompted us to verify their resemblance at the structural level. The modelled ORF8 protein was found to superimpose on the F1 fragment. Further, protein-protein interaction simulation confirmed ORF8 binding to C3b, an endogenous substrate of F1, via F1-interacting region on C3b. Docking results suggest ORF8 to occupy the binding groove adjacent to the conserved "arginine-serine" (RS) F1-mediated cleavage sites on C3b. Comparative H-bond interaction dynamics indicated ORF8/C3b binding to be of higher affinity than the F1/C3b interaction. Hence, ORF8 is predicted to inhibit C3b proteolysis by competing with F1 for C3b binding using molecular mimicry with a possibility of triggering unregulated complement activation. This could offer a mechanistic premise for the unrestrained complement activation observed in large number of SARS-CoV-2 infected patients.

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Singh, J., Kar, S., Ganguly, S., Hasnain, S. E.. 2020-06-09. Molecular modelling predicts SARS-CoV-2 ORF8 protein and human complement Factor 1 catalytic domain sharing common binding site on complement C3b. https://doi.org/10.1101/2020.06.08.107011

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