Molecular dynamics studies on the effect of trifluoperazine in the Ca2+ binding process of calmodulin

Abstract A detailed investigation of the binding of trifluoperazine (TFP) to calmodulin (CAM) can give information on the loop-selectivity of the first Ca 2+ binding and determination of Ca 2+ cooperativity in the N-terminal domain. This information has been obtained by carrying out molecular dynamics simulations. By using interactive computer graphics, seven models for CAM are constructed according to sequential Ca 2+ occupancy and TFP occupancy. Analysis of the resulting structure shows that the binding site of the first Ca 2+ in the N-terminal domain is EFII rather than EFI. Electrostatic interactions between each Ca 2+ and its opposite loop play an important role in the cooperativity. TFP increases the Ca 2+ affinity and Ca 2+ cooperativity, and TFP prefers to bind to CAM with three rather than four bound Ca 2+ ions.