Effect of Ca2+ binding states of calmodulin on the conformational dynamics and force responses of myosin lever arm

The mechanochemical coupling and biological function of myosin motors are regulated by Ca2+ concentrations. As one of the regulation pathways, Ca2+ binding induces a conformational change of the light chain calmodulin and its binding modes with a myosin lever arm, which can affect the stiffness of the lever arm and force transmission. However, the underlying molecular mechanism of the Ca2+ regulated stiffness change is not fully understood. Here, we study the effect of Ca2+ binding on the conformational dynamics and stiffness of the myosin VIIa lever arm bound with a calmodulin by performing molecular dynamics simulations and dynamic correlation network analysis. The results showed that the calmodulin bound lever arm at an apo state can sample three different conformations. In addition to the conformation observed in a crystal structure, a calmodulin bound lever arm at the apo condition can also adopt other two conformations featured by different extents of small-angle bending of the lever arm. However, large-angle bending is strongly prohibited. Such results suggest that the calmodulin bound lever arm without Ca2+ binding is plastic for small-angle deformation but shows high stiffness for large-angle deformation. In comparison, after the binding of Ca2+, although the calmodulin bound lever arm is locally more rigid, it can adopt largely deformed or even unfolded conformations, which may render the lever arm incompetent for force transmission. The conformational plasticity of the lever arm for small-angle deformation at the apo condition may be used as a force buffer to prevent the lever arm from unfolding during the power stroke action of the motor domain.