Molecular dynamics simulation and MM-PBSA calculations of sickle cell hemoglobin in dimer form with Val, Trp, or Phe at the lateral contact

As the delay time and hence nuclei formation play a crucial role in the pathophysiology of sickle cell disease, MD simulation and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations have been performed on three systems of hemoglobin; namely dimer of hemoglobin with valine (Hb S), tryptophan (Hb beta 6W), and phenylalanine (Hb beta 6F) at beta 6 position. The structural changes due to these aromatic substitutions are investigated. It is shown that beta subunits have significant impact on the differences between a dimer and other crystal structures. Transition from a dimer to polymer for Hb S system affects the donor molecule more than that of the acceptor. In the case of donor and acceptor subunits, the RMSD values are ordered as Hb beta 6F > Hb beta 6W > Hb S which predicts a larger deviation for the Hb beta 6F dimer. It is shown that the formation of stable dimers is in the order of Hb beta 6F > Hb S > Hb beta 6W, but contribution of the beta 6 residue in Hb beta 6W is more than two other systems. This study shows that the interaction of beta 6 residue in Hb S is mostly van der Waals type, but in two other systems the electrostatic interaction is also noticeable, especially in the case of Hb beta 6W in which the hydrogen bond plays an important role in the association of monomers. Trp and Phe also have a stabilizing van der Waals interaction with a hydrophobic pocket composed of 1 beta 2-10Ala, 1 beta 2-125Pro, 1 beta 2-126Val, and 1 beta 2-129Ala. Our survey shows that the role of 2 beta(1)-85Phe is very important only in the nucleus formation of Hb S, but not for the subsequent processes. Copyright (C) 2010 John Wiley & Sons, Ltd.