Mutation Sites Are Distant from Remdesivir Binding Site in Human SARS-CoV-2 RNA-Dependent RNA Polymerase

The comparison of 10,929 human SARS-CoV-2 RdRp protein sequences representing six geographical locations with the reference protein sequence in human SARS-CoV-2 genome isolate from Wuhan, China, identified 222 distinct mutation sites in the RdRp protein. The NiRAN and interface domains, Fingers, Palm and Thumb sub-domains were each associated with ~20% or more mutations compared to mutations in N-terminal, beta-hairpin or C-terminal regions of the protein. The Pro4715Leu mutation was predominantly observed in RdRp proteins from all six geographical locations; Africa, Asia, Europe, North America, Oceania and South America. None of the mutation site residues were within 3.2 Å interacting distance from remdesivir as observed in the three-dimensional cryo-electron microscopy structures of RdRp protein complexes available in the Protein Data Bank. Therefore, the mutations in human SARS-CoV-2 RdRp proteins, described in the present work, are not likely to cause resistance to remdesivir binding. Further, the mutations were also not associated with functionally important residues that would affect the enzyme’s function.