Antibody accessibility determines location of spike surface mutations in SARS-CoV-2 variants

Figures

• 

  Fig 1. SARS-CoV-2 spike mutations and accessibility scores. Mutated residues in spike variants are marked by colored squares above the plot. Open squares indicate mutations at the furin cleavage site and D614G. The consensus epitope score of [18] is shown in orange, and the AAS considering glycans in blue. Grey shading in the plot indicates surface residues as listed in S1 Table. Variants are distinguished by color, as indicated in the legend. The N-terminal domain (NTD) and receptor-binding domain (RBD) are indicated at the bottom, as are the S1/S2 furin cleavage site (vertical dashed line) and the S2′ site (solid vertical line).

• 

  Fig 2. Mutations in the spike protein of SARS-CoV-2 variants concentrate in regions of high epitope and accessibility scores. Top views (A, B) and side views (C, D) of spike. Pink spheres show positions of Omicron BA.1 mutations, red spheres show positions unique to Omicron BA.5 mutations, and yellow spheres are those in earlier variants. Intense purple surface shading in A and C indicates high consensus epitope score [18]. Intense cyan surface shading in B and D indicates high AAS. Structures are snapshots from earlier MD simulations [19]. Proteins were rendered with Visual Molecular Dynamics (VMD) v1.9.3 [20].

• 

  Fig 3. Epitope and antibody accessibility scores discriminate between spike mutation sites and generic surface residues. CDFs of (A) the epitope consensus score [18] and (B) the AAS considering glycans and calculated for all spike residues (black), surface residues (blue), sites of mutations in Omicron BA.1 (green), Omicron BA.5 (purple), and earlier variants (orange). Red arrows indicate the KS statistic as the maximum vertical gap between the CDFs for Omicron BA.1 mutation sites and surface residues, respectively. The corresponding P-values for the epitope score (A) and the AAS (B) are 0.016 and 1.5 × 10−5, respectively.

• 

  Fig 4. Immune escape mutations have high accessibility scores. CDFs of AAS are shown for mutations that were shown experimentally by Cao et al. [7] to reduce binding to neutralizing antibodies (gold). For reference, we show AAS distributions of surface residues (blue) and all residues (black) of spike, as well as all RBD surface residues (brown). Score distributions were calculated (A) without glycans and (B) with glycans. The KS statistic is the maximum vertical gap between the respective CDFs and is indicated by a red arrow in (B).

• 

  Fig 5. Mutations in emerging variants lower antibody access score on the surface of SARS-CoV-2 spike relative to WT and earlier variants. Spike renders with color intensity (white to red) indicating AAS, in which the AAS is set to zero in regions within 1 nm of a mutated site with respect to the reference sequence. (A, E): “Naive” antibody access by antibodies produced after (A) first WT vaccination (no previous infection) or (E) first infection by any variant (no previous vaccination). We assume here that all variants confer approximately the same accessibility to antibodies of naive hosts, and renders in (A) and (E) are identical. (B-D) Calculated reduction of AAS for antibodies produced against WT vaccination. (F) Calculated reduction of AAS for antibodies produced against BA.1 infection. Blue circles indicate notable reductions in AAS. Regions are labeled according to epitope candidates in [18]. N: N-terminus. In these renders, the AAS was set to zero for amino acids within 1 nm of any amino acid that was mutated with respect to the reference sequence.