Dominant Clade-featured SARS-CoV-2 Co-occurring Mutations Reveals Plausible Epistasis: An in silico based Hypothetical Model.

SARS-CoV-2 is evolved into eight fundamental clades where four (G, GH, GR, and GV) are globally prevalent in 2020. To explain plausible epistatic effects of the signature co-occurring mutations of these circulating clades on viral replication and transmission fitness, we proposed a hypothetical model using in silico approach. Molecular docking and dynamics analyses showed the higher infectiousness of a spike mutant through more favorable binding of G614 with the elastase-2. RdRp mutation p.P323L significantly increased genome-wide mutations (p<0.0001), providing that more flexible RdRp (mutated)-NSP8 interaction may accelerate replication. Superior RNA stability and structural variation at NSP3:C241T might impact protein, RNA interactions, or both. Another silent 5'UTR:C241T mutation might affect translational efficiency and viral packaging. These four G-clade-featured co-occurring mutations might increase viral replication. Sentinel GH-clade ORF3a:p.Q57H constricted ion-channel through inter-transmembrane-domain interaction of cysteine(C81)-histidine(H57) and GR-clade N:p.RG203-204KR would stabilize RNA interaction by a more flexible and hypo-phosphorylated SR-rich region. GV-clade viruses seemingly gained the evolutionary advantage of the confounding factors; nevertheless, N:p.A220V might modulate RNA binding with no phenotypic effect. Our hypothetical model needs further retrospective and prospective studies to understand detailed molecular events featuring the fitness of SARS-CoV-2. This article is protected by copyright. All rights reserved.