Molecular dynamics analysis of structural factors influencing back door Pi release in myosin
Molecular dynamics analysis of structural factors influencing back door Pi release in myosin
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DOI：
10.1529/biophysj.103.037390
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发表时间：
2004-06-01
影响因子：
3.4
通讯作者：
Yount, RG
中科院分区：
文献类型：
--
作者：
Lawson, JD;Pate, E;Yount, RG
已经提出了从肌球蛋白活性位点退出由腺苷5'-三磷酸水解产生的磷酸（P-i）的后门。我们使用分子动力学模拟来研究P-i与后门的相互作用以及通过该途径释放P-i的可行性。用结合Mg的分子动力学方法模拟了盘齿柱的运动结构域。5'-二磷酸腺苷（ADP）和P-i，模拟Mg.ADP. befx和Mg.ADP。vi结构。模拟结果表明，AIDP和自由Pi从初始位置的弛豫分别通过位于50 kda上下子域的开关1和开关2的运动减小了后门的直径。在这两个模拟中，P-i都不能自由扩散到后面。门。然而，水分子可以通过Mg.ADP的后门流动。基于befx的仿真，而不是在Mg.AIDP。V-i-based模拟。在两个结构中都没有观察到水通过主（前门）入口。这些观察结果表明，P-i通过后门离开的能力与上下50 kda子结构域之间的构象变化密切相关。模拟提供了o -18在活性位点与P-i交换的结构解释，以及P-i释放是肌球蛋白腺苷5'-三磷酸酶的限速步骤。
The back door has been proposed to bean exit pathway from the myosin active site for phosphate (P-i) generated by adenosine 5'-triphosphate hydrolysis. We used molecular dynamics simulations to investigate the interaction of P-i with the back door and the plausibility of P-i release via this route. Molecular dynamics simulations were performed on the Dictyostelium motor domain with bound Mg.adenosine 5'-diphosphate (ADP) and P-i, modeled upon the Mg.ADP.BeFx and Mg.ADP.V-i structures. Simulations revealed that the relaxation of AIDP and free Pi from their initial positions reduced the diameter of the back door via motions of switch 1 and switch 2 located in the upper and lower 50-kDa subdomains, respectively. In neither simulation could P-i freely diffuse out the back. door. Water molecules, however, could flux through the back door in the Mg.ADP.BeFx-based simulation but not in the Mg.AIDP.V-i-based simulation. In neither structure was water observed fluxing through the main (front door) entrance. These observations suggest that the ability of P-i to leave via the back door is linked tightly to conformational changes between the upper and lower 50-kDa subdomains. The simulations offer structural explanations for O-18-exchange with P-i at the active site, and P-i release being the rate-limiting step in the myosin adenosine 5'-triphosphatase.