Critical residues responsible for self-association differences of hemoglobin alpha and beta chains: analysis by molecular modeling.

Although the alpha and beta chains of adult human hemoglobin (Hb A) are very similar, when isolated the individual chains display marked differences in the propensities to form homotetramers: alpha chains alone associate weakly into dimers, while beta chains form relatively stable tetramers. We have examined the origin of this difference using computer-based model building and energy minimization. For oxyhemoglobin (R state) structures, interfaces have been compared for energy minimized alpha 2 beta 2, beta 4, and hypothetical alpha 4 tetramers. For the alpha 1-beta 1 interface (also designated as the X-interface) 19 alpha chain and 19 beta chain residues were identified that each contribute at least 1% to the energy of the contact in Hb A. This interface has a high degree of pseudo-symmetry, with identical residues at 6 of these positions for both chains. The geometry of the X-interface is similar for the homotetramers, with all 6 of these residues retained at the interface in beta 4 and 4 of the 6 found at the interface in alpha 4, although the alpha-alpha interface involves fewer contacts and less buried surface area. For the alpha 1-beta 2 interface (also designated as the Z-interface) 10 alpha chain and 10 beta chain residues are identified as contributing at least 1% to the energy of the contact in Hb A; about half of the contact residues are identical for corresponding positions of alpha and beta chains and most of these residues are retained at the interfaces in the two types of homotetramers, but with fewer alpha-alpha contacts.