Shimoyama Hiromitsu, Shigeta Yasuteru
Center for Computational Sciences, Unviersity of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
Life (Basel). 2021 Nov 16;11(11):1241. doi: 10.3390/life11111241.
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 Ca 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.
钙调蛋白（CaM）是一种多功能钙结合蛋白，可调节多种生化过程。CaM通过其构象变化以及与靶酶形成复合物来发挥作用。CaM由两个球状结构域（N叶和C叶）通过一个延伸的连接区域相连组成。钙离子结合后，N叶和C叶会发生局部构象变化，随后整个CaM会发生重大构象变化以包裹靶酶。然而，调节这些大的结构变化的变构相互作用等调节机制仍不清楚。为了研究这一系列结构变化，通过多尺度分治分子动力学（MSDC-MD）获得了CaM的自由能景观。所得的自由能景观（FEL）表明，结合钙离子的CaM（全酶CaM）会呈现出一种在实验中著名的伸长结构，这种结构可在结构变化的早期通过打破结构域间相互作用而形成。FEL还表明，重要的相互作用完成了从伸长结构到环状结构的结构变化。此外，FEL可能为预测CaM中的突变位点提供指导原则。在本研究中，证明了FEL上宏观变量的运动过程在一定程度上可能是扩散性的，因此，MSDC-MD适用于并行计算。
