MOLECULAR-DYNAMICS OF SICKLE AND NORMAL HEMOGLOBINS

Molecular dynamics (MD) simulations have been carried out for 62.5 ps on crystal structures of deoxy sickle cell hemoglobin (HbS) and normal deoxy hemoglobin (HbA) using the CHARMM MD algorithm, with a time ste p of 0.001 ps. In the trajectory analysis of the 12.5-62.5 (50 ps) sim ulation, oscillations of the radius of gyration and solvent-accessible surface area were calculated. HbS exhibited a general contraction dur ing the simulation, while HbA exhibited a nearly constant size. The av erage deviations of simulated structures from the starting structures were found to be 1.8 angstrom for HbA and 2.3 angstrom for HbS. The av erage rms amplitudes of atomic motions (atomic flexibility) were about 0.7 angstrom for HbA and about 1.0 angstrom for HbS. The amplitudes o f backbone motion correlate well with temperature factors derived from x-ray crystallography. A comparison of flexibility between the alpha- and beta-chains in both HbA and HbS indicates that the beta-chains ge nerally exhibited greater flexibility than the alpha-chains, and that the HbS beta-chains exhibit greater flexibility in the N-terminal and D- and F-helix regions than do those of HbA. The average amplitude of backbone torsional oscillations was about 9-degrees, a value comparabl e with that of other simulations, with enhanced torsional oscillation occurring primarily at the ends of helices or in loop regions between helices. Comparison of atomic flexibility and torsional oscillation re sults suggests that the increased beta-chain flexibility results from relatively concerted motions of secondary structure elements. The incr eased flexibility may play an important role in HbS polymerization. Ti me course analysis of conformational energy of association, hydrogen b onding and hydrophobic bonding (as calculated from solvent accessibili ty) shows that all three of these factors contribute to the stability of subunit association for both hemoglobins.