Allosteric communication between distant parts of protein controls many cellular functions. Binding of Ca2+ to the helix-loop-helix motifs (termed EF-hands) in calmodulin (CaM) leads to large conformational changes poising it for the binding of target proteins involved in a variety of cell signaling events. Despite the physiological importance, the mechanism of Ca2+-mediated allosteric transitions in CaM remains elusive. Particularly, it is still unclear how water molecules contribute to Ca2+ coordination and the coupled conformational motions. We use all-atom molecular dynamics simulations with enhanced sampling method to investigate the coupling between the Ca2+ binding, dehydration, and the conformational change of the isolated CaM domains, each containing two EF-hands. We reveal a water-bridged coordination mechanism during Ca2+ binding and dehydration, in which the bridging water molecules reduce the entropy penalty during the coordination of liganding residues, thus contributing to efficient ligand binding in CaM domains. Exposure of hydrophobic sites occurs by calcium-induced rotation of the helices of EF-hands with the hydrophobic core serving as the pivot. Interestingly, we find that despite being structurally similar, the structural response in the two EF-hands upon Ca2+ binding is highly asymmetric, which is needed for allosteric communication between them. The atomically detailed picture for the allosteric transitions of the CaM EF-hands, which are the first events in mediating a variety of intracellular processes, reveal the complex interplay between the discrete water molecules, dehydration of Ca2+, and CaM structural changes.
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