Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
J Chem Phys. 2011 Feb 28;134(8):085103. doi: 10.1063/1.3544209.
A set of techniques developed under the umbrella of the string method is used in combination with all-atom molecular dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI. The challenges specific to the application of these techniques to such a large and complex biomolecule are addressed in detail. These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition. A detailed description of the PPS↔R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion. The methodology developed here is expected to be useful more generally in studies of conformational transitions in complex biomolecules.
一套在弦方法的框架下开发的技术与全原子分子动力学模拟相结合，用于分析肌球蛋白 VI 变构域预功构象（PPS）和刚性（R）结构之间的构象变化。这些技术应用于如此大而复杂的生物分子所特有的挑战得到了详细解决。这些挑战包括：（i）确定一组合适的集总变量来应用弦方法；（ii）找到合适的初始弦；（iii）获得过渡路径上自由能的收敛分布；（iv）验证和解释自由能分布；（v）计算过渡的平均首次通过时间。详细描述了肌球蛋白 VI 变构域中的 PPS↔R 转变，包括转变路径、路径上的自由能以及相互转换的速率。这里开发的方法有望在复杂生物分子构象转变的研究中更普遍地得到应用。
