Department of Biomedical Engineering, Wayne State University, 818 W. Hancock St., Detroit, MI 48201, USA.
J Mol Model. 2013 Feb;19(2):779-92. doi: 10.1007/s00894-012-1604-z. Epub 2012 Oct 10.
The unique conformation of the active site in calpains along with the implication of their role in several diseases has prompted widespread research interest in the scientific community. Structural studies devoted to m- and μ-calpains have proposed a two-stage calcium-dependent activation mechanism for calpains. In this work, we performed conventional and targeted molecular dynamics simulations to investigate global and local changes in the structure of the protease core of m-calpain upon calcium binding. Simulations were performed on the protease core of calcium free (pdbid: 1kfu) and calcium bound (pdbid: 3df0) m-calpain with and without the presence of calcium ions. Our results indicate that the inactive, open conformation of the protease core does not transform into the active, closed conformation simply upon removal of constraints from the neighbor domains. The role of other factors, including calcium binding and the subsequent formation of an Arg94-Glu305 inter-domain salt bridge and the change in the orientation of Trp288 side chain, in the activation of the protease core is elicited.
钙蛋白酶的活性位点的独特构象以及其在多种疾病中的作用暗示，这促使科学界广泛关注钙蛋白酶。致力于 m- 和 μ-钙蛋白酶的结构研究提出了钙蛋白酶的两步钙离子依赖性激活机制。在这项工作中，我们进行了常规和靶向分子动力学模拟，以研究钙结合后 m-钙蛋白酶蛋白酶核心的整体和局部结构变化。模拟是在无钙（pdbid：1kfu）和钙结合（pdbid：3df0）m-钙蛋白酶的蛋白酶核心上进行的，有无钙离子存在。我们的结果表明，蛋白酶核心的无活性、开放构象在从相邻结构域去除约束后并不会简单地转变为活性的、封闭的构象。其他因素的作用，包括钙结合以及随后形成 Arg94-Glu305 结构域间盐桥和 Trp288 侧链取向的变化，在蛋白酶核心的激活中被引出。
