A Free-Energy Landscape Analysis of Calmodulin Obtained from an NMR Data-Utilized Multi-Scale Divide-and-Conquer Molecular Dynamics Simulation

Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon calcium binding, the N-lobe and C-lobe undergo local conformational changes, followed by a major conformational change of the entire CaM to wrap the target enzyme. However, the regulation mechanisms, such as allosteric interactions, which regulate the large structural changes, are still unclear. In order to investigate the series of structural changes, the free-energy landscape of CaM was obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD). The resultant free-energy landscape (FEL) shows that the Ca2+ bound CaM (holo-CaM) would take an experimentally famous elongated structure, which can be formed in the early stage of structural change, by breaking the inter-domain interactions. The FEL also shows that important interactions complete the structural change from the elongated structure to the ring-like structure. In addition, the FEL might give a guiding principle to predict mutational sites in CaM. In this study, it was demonstrated that the movement process of macroscopic variables on the FEL may be diffusive to some extent, and then, the MSDC-MD is suitable to the parallel computation.