School of Pharmacy, Kitasato University, Tokyo, Japan.
High Pressure Protein Research Center, Institute of Advanced Technology, Kindai University, Wakayama, Japan.
J Comput Chem. 2021 Jan 5;42(1):19-26. doi: 10.1002/jcc.26429. Epub 2020 Oct 8.
Calcineurin (CaN) is a eukaryotic serine/threonine protein phosphatase activated by both Ca and calmodulin (CaM), including intrinsically disordered region (IDR). The region undergoes folding into an α-helix form in the presence Ca -loaded CaM. To sample the ordered structure of the IDR by conventional all atom model (AAM) molecular dynamics (MD) simulation, the IDR and Ca -loaded CaM must be simultaneously treated. However, it is time-consuming task because the coupled folding and binding should include repeated binding and dissociation. Then, in this study, we propose novel multi-scale divide-and-conquer MD (MSDC-MD), which combines AAM-MD and coarse-grained model MD (CGM-MD). To speed up the conformation sampling, MSDC-MD simulation first treats the IDR by CGM to sample conformations from wide conformation space; then, multiple AAM-MD in a limited area is initiated using the resultant CGM conformation, which is reconstructed by homology modeling method. To investigate performance, we sampled the ordered conformation of the IDR using MSDC-MD; the root-mean-square distance (RMSD) with respect to the experimental structure was 2.23 Å.
钙调神经磷酸酶（CaN）是一种真核丝氨酸/苏氨酸蛋白磷酸酶，可被 Ca 和钙调蛋白（CaM）激活，包括无规则结构域（IDR）。在存在 Ca 负载的 CaM 的情况下，该区域折叠成α-螺旋形式。为了通过传统的全原子模型（AAM）分子动力学（MD）模拟来采样 IDR 的有序结构，必须同时处理 IDR 和 Ca 负载的 CaM。然而，由于偶联的折叠和结合应包括重复的结合和解离，这是一项耗时的任务。然后，在这项研究中，我们提出了新的多尺度分而治之 MD（MSDC-MD），它结合了 AAM-MD 和粗粒化模型 MD（CGM-MD）。为了加快构象采样，MSDC-MD 模拟首先通过 CGM 处理 IDR，从宽构象空间中采样构象；然后，使用同源建模方法重建 CGM 构象，在有限区域中启动多个 AAM-MD。为了研究性能，我们使用 MSDC-MD 对 IDR 的有序构象进行了采样；与实验结构的均方根偏差（RMSD）为 2.23Å。
