New insights into the allosteric mechanism
of human hemoglobin from
molecular dynamics simulations
*Institut Curie, INSERM U350, Bât. 110-112,
Université Paris-Sud. 91405 Orsay cedex
It is still difficult to obtain a precise structural description of the transition between the deoxy T-state and oxy R-state conformations of human hemoglobin, despite a large number of experimental studies. We used molecular dynamics with the PEDC method (Path Exploration with Distance Constraints) to provide new insights into the allosteric mechanism at the atomic level, by simulating the T-to-R transition.
The T-state molecule in the absence of ligands was seen to have a
natural propensity for dimer rotation, which nevertheless would be hampered by
steric hindrance in the “joint” region. The binding of a ligand to the a subunit would prevent such hindrance due to the coupling between this
region and the a proximal histidine, and thus
facilitate completion of the dimer rotation. Near the end of this quaternary
transition, the “switch” region adopts the R conformation resulting in a shift
of the b proximal histidine. This
leads to a sliding of the b-heme, the effect of which
is to open the b-heme's distal side, increasing the accessibility of the Fe atom and
thereby the affinity of the protein. Our simulations are globally consistent
with the Perutz strereochemical mechanism.