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

Abstract

A SARS-CoV-2 lineage designated as Theta (P.3) with 16 signature mutations in the Spike protein region has been reported with cases centered in Region 7 of the Philippines. Whole-genome sequencing revealed that the 33 samples under this lineage all contain the E484K, N501Y, and P681H Spike mutations previously found in the SARS-CoV-2 variants of concern (VOCs): Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1). This report focuses on possible implications of the mutations found in the Spike protein based on the analysis of the Theta variant’s structure, stability, and molecular surface character. The analyses included investigations using static models and molecular dynamic simulations between the Spike protein receptor-binding domain (RBD) and its interactions with the angiotensin-converting enzyme II (ACE2) receptor. Our results suggest that these mutations could significantly impact the possible interactions of the Spike protein with the ACE2 receptor and neutralizing antibodies, and warrants further clinical investigation. Some of the mutations affecting the N and C terminal domains suggest 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 within the Philippines.