Allosteric Mechanism of Calmodulin Revealed by Targeted Molecular Dynamics Simulation

Calmodulin (CaM) is involved in the regulation of a variety of cellular signaling pathways. To accomplish its physiological functions, CaM binds with Ca^2+ at its EF-hand Ca^2+ binding sites which induce the conformational switching of CaM. However, the molecular mechanism by which Ca^2+ binds with CaM and induces conformational switching is still obscure. Here we combine molecular dynamics with targeted molecular dynamics simulation and achieve the state-transition pathway of CaM. Our data show that Ca^2+ binding speeds up the conformational transition of CaM by weakening the interactions which stabilize the closed state. It spends about 6.5 ns and 5.25 ns for transition from closed state to open state for apo and holo CaM, respectively. Regarding the contribution of two EF-hands, our data indicate that the first EF-hand triggers the conformational transition and is followed by the second one. We determine that there are two interaction networks which contribute to stabilize the closed and open states, respectively.