Abstract
It has been demonstrated that mutant Hemoglobins (Hb) which have an altered ${\alpha}$1${\beta}$2 subunit interface can be designed. A compensatory mutation for a naturally occurring abnormal human Hb, Hb Kempsey (${\beta}$99Asp\longrightarrowAsn), has been designed, and this mutation allowed the molecule to regain its allosteric response. The calculated values for the difference in the free energy of cooperativity show excellent agreement with experimentally determined thermodynamic values, suggesting that the molecular dynamics simulation results can be used to obtain information about the specific interactions which contribute to the total free energy of cooperativity. These results provide encouragement to begin a systematic investigation of the molecular basis of the subunit interactions between the ${\alpha}$1 and ${\beta}$2 chains of Hb A by designing appropriate r Hbs. These studies could lead to the design of Hbs with desired cooperativity in the oxygenation process and to the restoration of functional properties of abnormal hemoglobins associated with hemoglobinopathies. Thus, the present results also have the implications in using gene therapy to treat patients with hemoglobinpathies.