Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide

Abstract

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD–ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD–ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.

Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach

“…A570D: The A570D substitution was first identified in the B.1.1.7 UK variant (Alpha or GRY GR/501Y.V1) in December 2020. Along with D614G, this mutation induces significant conformational destabilization ( Socher et al., 2021 ).…”

Two-Component Nanoparticle Vaccine Displaying Glycosylated Spike S1 Domain Induces Neutralizing Antibody Response against SARS-CoV-2 Variants

“…The neutralizing antibody titer determinations have been performed in separate assays and, thus, cannot be directly compared, but it is feasible that protection against B.1.1.7 is somewhat reduced due to the presence of several mutations in the S1 domain (HV69-70del, Y144del, N501Y, A570D, and D614G). With RBD-based vaccines, this difference would only be a single amino acid (N501Y) ( 68 ). Immunogenicity against current and emerging variants might be further improved by the development of a multivalent vaccine, i.e., a VLP displaying a mixture of S1 variants.…”

Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

“…However, the sterical hindrance of the tyrosine might introduce perturbation at the interface. In fact, very recently Socher et al [35] performed molecular dynamics simulations also on this substitution showing a reduced binding affinity of B.1.1.7 Sp for ACE2, as the residue Y501 de-restructured the Sp-ACE2 interface decreasing the linear interaction energy between the RBD and ACE2.…”

“…The close spatial proximity of D30-K417 and K31-E484 opposite-charge couples suggests that the double mutation observed in Beta and Gamma variants (i.e., K417N and E484K) removed the two interactions, but maintained in the region at least the positive lysine side chain on the SARS-CoV-2 surface, which might preserve in that region at least one opposite-charge couple. However, the molecular impact of mutations within RBD on Sp binding stability with ACE2 is yet largely unknown and needs further investigations [35]. 1a; black = amino acids listed in Table 1b; green and blue = amino acids listed in Table 1c (for SARS-CoV-2 and CoV-1, respectively); orange = amino acid of Sp SARS-CoV-1 also listed in Table 1c with a peculiar feature (see Table 1 note).…”