AN ALLOSTERIC THEORY FOR HEMOGLOBIN INCORPORATING ASYMMETRIC STATES TO TEST THE PUTATIVE MOLECULAR CODE FOR COOPERATIVITY

The two-state (MWC) model for cooperative oxygen binding by tetrameric (alpha(2) beta(2)) hemoglobin based on concerted transitions between symmetric states (T and R) is extended to include a third, asymmetric state with one alpha beta dimer possessing high (R-like) oxygen affini ty and the other alpha alpha dimer possessing low (T-like) oxygen affi nity. The asymmetric state is assigned a stability that corresponds to the level reported by Ackers and colleagues in the studies on mixed v alence hybrids that led to their proposed ''molecular code for coopera tivity in hemoglobin.'' However, this level of stability for the asymm etric intermediates significantly diminishes cooperativity in simulate d oxygenation curves, to a degree (Hill n = 2.1) that is no longer com patible with the well-established oxygenation properties of normal fer rous hemoglobin (Hill n similar to 3.0). Therefore, the cyanomet deriv atives do not appear to be reliable analogues of intermediate oxygenat ion states. (C) 1996 Academic Press Limited