Molecular dynamics simulations were performed to calculate the difference between the dimerization free energies of normal human deoxyhemoglobin (HbA) and the mutant sickle-cell deoxyhemoglobin HbS (Glu-beta 6----Val) for one of the lateral contacts in the HbS x-ray structure. The simulations yield a value of--15 kcal/mol. Although there is no quantitative experimental value for comparison, this is in qualitative agreement with the experimental result that HbS self-assembles into multistranded fibers that are responsible for erythrocyte sickling, while HbA does not. The free-energy difference was decomposed into enthalpic and entropic terms, both of which are significant, and the contributions of individual protein residues and of the solvent were examined. Electrostatic effects play the dominant role in favoring dimerization of HbS compared with HbA; van der Waals interactions make a negligible contribution to the difference. Both differential solvation and protein-protein interactions are important. Interactions within the donor tetramer (i.e., that containing the Glu-beta 6 mutation site), as well as those with the acceptor tetramer, contribute to the preferential free energy of dimerization of HbS.