Structural Analysis of Spike Protein Mutations in the SARS-CoV-2 P.3 Variant

Abstract

A SARS-CoV-2 emergent lineage with multiple signature mutations in the Spike protein region was recently reported with cases centered in Cebu Island, Philippines. Whole genome sequencing revealed that the 33 samples with the Ph-B.1.1.28 emergent variant merit further investigation as they all contain the E484K, N501Y, and P681H Spike mutations previously found in other variants of concern such as the South African B.1.351, the Brazil P.1 and the UK B.1.1.7 variants. This is the first known report of these mutations co-occurring in the same virus. The possible implications of the mutations found in the Spike protein were analyzed for their potential effects on structure, stability, and molecular surface character. The analysis suggests that these mutations could significantly impact the possible interactions of the Spike protein monomer with the ACE2 receptor and neutralizing antibodies and warrants further clinical investigation. Some of the mutations affecting the N and C terminal domains may have effects on Spike monomer and trimer stability. This report provides insights on relevant targets for the design of future diagnostics, therapeutics and vaccines against the evolving SARS-CoV-2 variants in the Philippines.

Molecular Level Dissection of Critical Spike Mutations in SARS‐CoV‐2 Variants of Concern (VOCs): A Simplified Review

“…Since this 484 th Moreover, during RBD-hACE2 binding this loop shift leads to formation of additional hydrogen bonding interactions in the compatible residues. [72,73] Thus more favourable electrostatic interactions and formation of new hydrogen bonds due to E484K mutations, provides additional stability to the RBD-hACE2 binding. [74] The aforementioned improved affinity is a likely culprit for more rapid spread of this variant due to greater transmissibility, which is a prime reason why it is important to track these mutations and act in a timely manner.…”

“…Figure 13), which leads to the extra stabilization of canonical FCS and in turn assists in more efficient recognition and cleavage finally resulting in better transmissibility. [73,89,90,91] The P681H mutation also results in a slight enhancement of polar character (due to Histidine) which in turn increases the stability in aqueous environments, and alters the neutralizing antibody binding properties. [73] In other case when proline (P) at 681 st residual position is replaced with arginine (R) (P681R), results in further enhancement of the basicity of the poly-basic stretch (RRAR), which might help in increased rate of membrane fusion, internalization and thus better transmissibility.…”

“…Moreover, during RBD‐hACE2 binding this loop shift leads to formation of additional hydrogen bonding interactions in the compatible residues [72,73] . Thus more favourable electrostatic interactions and formation of new hydrogen bonds due to E484K mutations, provides additional stability to the RBD‐hACE2 binding [74] .…”

“…Moreover, there is an increased contact between H681 and R683 residue after the mutation (viz. Figure 13), which leads to the extra stabilization of canonical FCS and in turn assists in more efficient recognition and cleavage finally resulting in better transmissibility [73,89,90,91] …”

“…Figure 13 ), which leads to the extra stabilization of canonical FCS and in turn assists in more efficient recognition and cleavage finally resulting in better transmissibility. [ 73 , 89 , 90 , 91 ]…”