Abstract
Cooperative binding of ligands to proteins can serve to increase their efficiency and to regulate their activity. Thus, understanding of the mechanism of cooperativity is one of the central concerns of molecular biology. For the tetrameric human hemoglobin (HbA), the cooperative mechanism involves a reasonably well understood combination of tertiary and quaternary changes that occur during the binding process. The dimeric hemoglobin ofScapharca (HbI), which is composed of subunits with a similar fold, is also highly cooperative but the structural changes on ligand binding are small. A reorientation of Phe 97 in the binding pocket and changes in the number of interfacial waters have been implicated in the cooperative mechanism. To explore the role of these factors, we have investigated partially liganded intermediate states of HbI with molecular dynamics simulation methods. Since, unlike HbA, no structures for intermediates are available, they were constructed by combining subunits from the unliganded and liganded dimers. Two structurally distinct intermediates were examined, and it was shown that the transition between the two intermediates is directly coupled to the number of interfacial water molecules. Further, it was found that there is a well-defined water channel that connects the interface between the subunits to bulk water. The bottleneck (gate) of the channel is made of hydrophilic residues that can open or close. The implication of the present results for the cooperative mechanism of HbI is discussed.
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