Inhibition of sickle β-Chain (β^S)-dependent polymerization by nonhuman α-chains

Abstract

Horse α-chain inhibits sickle β-chain-dependent polymerization; however, its inhibitory potential is not as high as that of mouse α-chain. Horse α-(1-30) and α-(31-141) segments make, respectively, minor and major contributions to the inhibitory potential of horse α-chain. The sum of the inhibitory potential of the two segments does not account for the inhibitory potential of the full-length horse α-chain. Although the polymerization inhibitory potential of horse α-chain is lower than mouse α-chain, the inhibitory potential of horse α-(31-141) is comparable to that of mouse α-(31-141). When mouse α-(1-30) is stitched to horse α-(31-141), the product is a chimeric α-chain with an inhibitory potential greater than mouse α-chain. In contrast, the stitching of horse α-(1-30) with mouse α-(31-141) had no additional inhibitory potential. Molecular modeling studies of HbS containing the mouse-horse chimeric α-chain indicate altered side-chain interactions at the α₁β₁ interface when compared with HbS. In addition, the AB/GH corner perturbations facilitate a different stereochemistry for the interaction of the ε-amino group of Lys-16(α) with the β-carboxyl group of Asp-116(α), resulting in a decrease in the accessibility of the side chain of Lys-16(α) to the solvent. Based on molecular modeling, we speculate that these perturbations by themselves, or in synergy with the altered conformational aspects of the α₁β₁interactions, represent the molecular basis of the superinhibitory potential of the mouse-horse chimeric α-chains.