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 dietal heme perturbations acro ss the alpha(1)beta(1) interface. Molecular dynamics simulations have been used to explain the molecular basis for these processes, Using a human meth emoglobin ap dimer, it has been shown that at 235 K after 61 ps, a rearrang ement Occurs in the alpha-chain corresponding to the formation of a bond wi th the distal histidine, This transition does not take place in the beta-ch ain 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 alpha beta interface. A detailed ana lysis of the simulation has been performed in terms of RMS fluctuations, do main cross-correlation maps, the disruption of helix hydrogen bonds, as wel l:changes in electrostatic interactions and dihedral angles. This analysis shows that the rearrangements in the alpha-chain necessary to bring the his tidine closer to their on involve alterations primarily in the CD loop and at the interface. Communication to the beta-chain distal pocket is propagat ed 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 alpha(1)beta(1) inter face extend into the alpha(1)beta(2) interfaces, providing a mechansim wher eby distal interactions can modulate the T reversible arrow R transition in hemoglobin.