Molecular dynamics of human methemoglobin: the transmission of conformational information between subunits in an alpha beta dimer.

Spectroscopic studies indicate an interaction of the distal histidine with the heme iron as well as the transmission of distal heme perturbations across the alpha1beta1 interface. Molecular dynamics simulations have been used to explain the molecular basis for these processes. Using a human methemoglobin alpha beta dimer, it has been shown that at 235 K after 61 ps, a rearrangement occurs in the alpha-chain corresponding to the formation of a bond with the distal histidine. This transition does not take place in the beta-chain during a 100-ps simulation and is reversed at 300 K. The absence of the distal histidine transition in the isolated chains and with the interface frozen indicate the involvement of the alphabeta interface. A detailed analysis of the simulation has been performed in terms of RMS fluctuations, domain cross-correlation maps, the disruption of helix hydrogen bonds, as well changes in electrostatic interactions and dihedral angles. This analysis shows that the rearrangements in the alpha-chain necessary to bring the histidine closer to the iron involve alterations primarily in the CD loop and at the interface. Communication to the beta-chain distal pocket is propagated by increased interactions of the alpha-chain B helix with the beta-chain G-GH-H segment and the flexibility in the EF loop. The G helices shown to be involved in propagation of perturbation across the alpha1beta1 interface extend into the alpha1beta2 interfaces, providing a mechansim whereby distal interactions can modulate the T<==>R transition in hemoglobin.