Biophys. J. 78, p.394A (2000).

K. Olsen, S. Fischer, M. Karplus.

Using the Conjugate Peak Refinement method (Fischer & Karplus, Chem. Phys. Let. (1992) 194:252), we have calculated the first continuous and energetically plausible path for the allosteric transition of hemoglobin.This simulation gives a sequence of events linking the T- and R-states in atomic detail, which can be compared to the stereochemical mechanism proposed by Perutz (Nature (1970) 228:726).We find that the important salt bridges break early before the HC2 Tyr residues move out of their pockets and before the major quaternary change, in which the b1His97 moves past the a2Val41 (the switch).This switch at the a1b2 interface is synchronous with the corresponding switch at the a2b1 interface.While these changes occur as predicted by Perutz, there are several aspects of the transition that could not have been anticipated by just comparing the crystallographic end-states.The distal His of the b-chains move out of the oxygen binding pocket and form a hydrogen bond to the mainchain carbonyl of bLys59 early in the path and then return to their original positions after the switch.The global C2 symmetry between the two ab dimers is retained during the entire transition, while most of the quaternary changes in the two a-chains occur significantly before the quaternary changes in the two b-chains.Visual inspection of the transition reveals that the G-helix of each a-chain serves as the rotation axis for its ab dimers.