Abstract
The ABO blood group system is the most important blood type system in human transfusion medicine. Here, we explore the specificity of antibody recognition toward ABO blood group antigens using computational modeling and biolayer interferometry. Automated docking and molecular dynamics simulations were used to explore the origin of the specificity of an anti-blood group A antibody variable fragment (Fv AC1001). The analysis predicts a number of Fv-antigen interactions that contribute to affinity, including a hydrogen bond between a HisL49 and the carbonyl moiety of the GalNAc in antigen A. This interaction was consistent with the dependence of affinity on pH, as measured experimentally; at lower pH there is an increase in binding affinity. Binding energy calculations provide unique insight into the origin of interaction energies at a per-residue level in both the scFv and the trisaccharide antigen. The calculations indicate that while the antibody can accommodate both blood group A and B antigens in its combining site, the A antigen is preferred by 4 kcal/mol, consistent with the lack of binding observed for the B antigen.
Highlights
Since its discovery in 1900 [1], the ABO blood group system has played a crucial role in defining human blood and tissue compatibility
We examined the structural origin of the antigenicity of a monoclonal antibody raised against blood group A (BGA) antigen, for which an apo structure of the single-chain variable fragment has been reported [17]
Upon inspection of the molecular dynamics (MD) data, it was observed that light chain residue His49 (HisL49) forms a stacking interaction with heavy chain residue Trp100 (TrpH100), which occupies a large volume of the presumed binding site, potentially preventing deeper penetration of the ligand (Figure 1)
Summary
Since its discovery in 1900 [1], the ABO blood group system has played a crucial role in defining human blood and tissue compatibility. The blood type of an individual indicates the presence or absence of relevant antigens and antibodies. The three blood types share a core oligosaccharide antigen (H), and based on the glycosyl transferases inherited, different antigens are synthesized [2,3,4]; type A transferase adds a terminal non-reducing N -acetylgalactosamine (GalNAc) residue; type B transferase adds galactose (Gal), whereas individuals with blood group O retain the unmodified H antigen. An A-type individual will have circulating antibodies specific for the B-antigen, and vice-versa. Because of the presence of circulating antibodies, a mismatched blood transfusion or organ transplant can lead to hyperacute immune response and death [5, 6]. Under certain circumstances, incompatibilities in blood groups between mother and child can trigger the mother’s immune system to produce antibodies against the fetus, causing hemolytic disease [7]
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