ENTHALPIC AND ENTROPIC CONTRIBUTIONS OF WATER-MOLECULES TO THE FUNCTIONAL T -] R TRANSITION OF HUMAN HEMOGLOBIN IN SOLUTION

Generalized solvent-mediated forces contribute to free energy at the functional T --> R transition of human hemoglobin A (HbA). Their contribution is here sorted out quantitatively in both its enthalpic and entropic parts, along with the average number of water molecules involved. The latter (about 75 waters in average) must be considered together with HbA as one statistically defined functional unit for oxygen transport. Their configurations are expected to undergo frequent structural rearrangements. Lifetimes of statistically relevant configurations do not need to (although, of course, they may) exceed by more than a factor 5 the normal H-bond lifetimes of the pure solvent. Compared to the bare protein, the "functional unit" here evidenced for the first time involves a larger, higher dimensionality region of the phase space. The study allows a microscopic view of solvent-mediated generalized forces and evidences their qualitative and quantitative relevance to biomacromolecular function and stability.