A molecular dynamics study of the effect of Ca²⁺ removal on calmodulin structure

Calmodulin is a small (148 residues), ubiquitous, highly-conserved Ca ²⁺ binding protein serving as a modulator of many calcium-dependent processes. In this study, we followed, by means of molecular dynamics, the structural stability of the protein when one of its four bound Ca²⁺ ions is removed, and compared it to a simulation of the fully Ca²⁺ bound protein. We found that the removal of a single Ca²⁺ ion from the N-lobe of the protein, which has a lower affinity for the ion, is sufficient to initiate a considerable structural rearrangement. Although the overall structure of the fully 4 Ca²⁺ bound protein remained intact in the extended conformation, the Ca²⁺-removed protein changed its conformation into a compact state. The observation that the 3 Ca²⁺ loaded protein assumes a compacted solution state is in accord with experimental observation that the NSCP protein, which binds only three Ca²⁺ ions, is natively in a compact state. Examination of the folding dynamics reveals a cooperation between the C-lobe, N-lobe,andthe interdomain helix that enable the conformation change.Theforces driving this conformationalchangeare discussed.