Figure 3.

A given allelic polymorphism can impact the binding activity of antibodies to different antigens

(A) The impact of the indicated paratope allelic polymorphisms on the antibody binding affinity of the corresponding antibodies is quantified by the fold change in the binding dissociation constant (K_D). A higher fold change indicates worse binding. Paratope allelic polymorphisms that abolished antibody binding are shown with a fold change of >100. Antibody specificity is color-coded.

(B and E) Allele usages of (B) IGHV1-69 antibodies and (E) IGLV3-21 antibodies are shown. The y axis represents the allele frequency among antibodies in GenBank that are encoded by the indicated V gene. Bar color represents the amino acid identity at the indicated residue position.

(C, D, F, and G) Structural effects of paratope allelic polymorphisms (C) V_H G50R of antibody 4E10 in complex with HIV Env membrane-proximal external region (PDB: 4XBE),³¹ (D) V_H G50R of antibody HC84.26.5D in complex with HCV glycoprotein E2 (PDB: 4Z0X),³² (F) V_L D50Y of antibody 5J8 in complex with influenza H1N1 A/California/07/2009 HA1 subunit (PDB: 4M5Z),³³ and (G) V_L D50Y of Fab234 in complex with C-terminal αTSR domain of P. falciparum circumsporozoite protein (PDB: 7RXI)³⁴ are modeled by FoldX.²¹ Left: previously determined experimental structures of antibody-antigen complexes. Right: models of alternative allelic polymorphisms. Allelic polymorphic residues are labeled in magenta. K_D values of wild-type and allelic mutants to antigens were measured by biolayer interferometry (BLI) and are indicated. N.B. represents no binding. Antibody heavy and light chains are shown in orange and yellow, respectively. Antigens are shown in white. Red disks indicate significant van der Waals overlap (distance < 2.8 Å), hence representing a steric clash. H-bonds are represented by black dashed lines. Kabat numbering is applied to all antibodies. Cα atoms of glycines are represented by spheres. The V-gene and allele usage for each antibody is indicated. Of note, the allele usage for HC84.26.5D cannot be assigned unambiguously.

See also Figures S2–S4 and Table S2.