Free-energy calculations along a high-dimensional fragmented path with constrained dynamics.
Free-energy calculations along a high-dimensional fragmented path with constrained dynamics.
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DOI：
10.1103/physreve.86.031901
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发表时间：
2012-09
期刊：
影响因子：
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通讯作者：
Changjun Chen;Yanzhao Huang;Yi Xiao
中科院分区：
文献类型：
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作者：
Changjun Chen;Yanzhao Huang;Yi Xiao
在高维体系（如多肽或蛋白质）的自由能计算中，在巨大的构象空间中存在严重的采样问题。对于这样的系统，基于路径的自由能方法，如热力学积分或自由能微扰，是很好的选择。然而，它们两者都需要沿着预定义的过渡路径沿着进行足够的采样，这只能使用受约束或受约束的动力学来控制。约束模拟比约束模拟产生更合理的自由能剖面。但是标准约束动力学的计算需要反应坐标作为所有相关原子的笛卡尔坐标的函数的显式表达式，这对于生物分子的复杂过渡可能很难找到。在本文中，我们提出了一个实用的解决方案：（1）我们使用约束动力学来定义一个优化的过渡路径，将其划分为小片段，并定义一个虚拟的反应坐标来表示沿路径的位置沿着。（2）我们使用约束动力学来执行一个正式的自由能计算每个片段，并收集值在一起，以提供完整的自由能剖面。该方法避免了在笛卡尔坐标系中明确定义反应坐标的要求，并提供了一种新的策略来执行自由能计算的生物分子沿着任何复杂的过渡路径。
Free-energy calculations for high-dimensional systems, such as peptides or proteins, always suffer from a serious sampling problem in a huge conformational space. For such systems, path-based free-energy methods, such as thermodynamic integration or free-energy perturbation, are good choices. However, both of them need sufficient sampling along a predefined transition path, which can only be controlled using restrained or constrained dynamics. Constrained simulations produce more reasonable free-energy profiles than restrained simulations. But calculations of standard constrained dynamics require an explicit expression of reaction coordinates as a function of Cartesian coordinates of all related atoms, which may be difficult to find for the complex transition of biomolecules. In this paper, we propose a practical solution: (1) We use restrained dynamics to define an optimized transition path, divide it into small fragments, and define a virtual reaction coordinate to denote a position along the path. (2) We use constrained dynamics to perform a formal free-energy calculation for each fragment and collect the values together to provide the entire free-energy profile. This method avoids the requirement to explicitly define reaction coordinates in Cartesian coordinates and provides a novel strategy to perform free-energy calculations for biomolecules along any complex transition path.