Genetic, Structural, Physicochemical, and Molecular Epidemiological Landscape of Three New Mutations Found in the Spike (S) Protein of Highly Transmissible Sri Lankan Delta Variant Sub-lineage AY.28: A222V, A701S, and A1078S

Abstract

Recently, three new mutations were identified in Sri Lanka in the spike protein of the rapidly spreading delta variant of the SARS-CoV-2 virus identified by the sublineage AY.28. They were A222V, A701S, and A1078S. The primary focus here is on the A701S mutation that is (1) found in the immediate vicinity of the S1/S2 cleavage site (PRRAR $\ast$ SV) that separates S1 and S2 subunits of the spike protein; (2) has high structural disorder of the region spanning Serine-701 (Ser-701), which promotes a longer flexible loop forming a better substrate; (3) collapses a loose, short, unstable, tripeptide beta strand (ENS), which is likely to assist the host proteases to cleave the S1-S2 interface easily than when an alanine is present. The same A701S mutation is found in at least 10 other strains of SARS-CoV-2 found in India, USA (East and West Coasts), and China, which classifies this mutation as geographically widespread and convergent in etiology. Conversely, the A1078S mutation is a highly present (>60 strains) mutation in terms of the SARS-CoV-2 coronaviruses, while the highly abundant A222V mutation is inferred by the genetic code, structural and topological features, and placement (in a beta strand) to be an innocuous, conservative mutation. The critical nature of S1/S2-dependent cleavage of S1 and S2 subunits of the spike protein makes the A701S mutation one of significance not just for possible higher virus transmission but also for subsequent fates such as viral load and vaccine effectivity against the delta variant.