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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >Extension of the Variational Free Energy Profile and Multistate Bennett Acceptance Ratio Methods for High-Dimensional Potential of Mean Force Profile Analysis
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Extension of the Variational Free Energy Profile and Multistate Bennett Acceptance Ratio Methods for High-Dimensional Potential of Mean Force Profile Analysis

机译：变分自由能谱和多岩Bennett接受比例的平均力分析分析的高维潜力

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摘要

We redevelop the variational free energy profile (vFEP) method using a cardinal B-spline basis to extend the method for analyzing free energy surfaces (FESs) involving three or more reaction coordinates. We also implemented software for evaluating high-dimensional profiles based on the multistate Bennett acceptance ratio (MBAR) method which constructs an unbiased probability density from global reweighting of the observed samples. The MBAR method takes advantage of a fast algorithm for solving the unbinned weighted histogram (UWHAM)/MBAR equations which replaces the solution of simultaneous equations with a nonlinear optimization of a convex function. We make use of cardinal B-splines and multiquadric radial basis functions to obtain smooth, differentiable MBAR profiles in arbitrary high dimensions. The cardinal B-spline vFEP and MBAR methods are compared using three example systems that examine 1D, 2D, and 3D profiles. Both methods are found to be useful and produce nearly indistinguishable results. The vFEP method is found to be 150 times faster than MBAR when applied to periodic 2D profiles, but the MBAR method is 4.5 times faster than vFEP when evaluating unbounded 3D profiles. In agreement with previous comparisons, we find the vFEP method produces superior FESs when the overlap between umbrella window simulations decreases. Finally, the associative reaction mechanism of hammerhead ribozyme is characterized using 3D, 4D, and 6D profiles, and the higher-dimensional profiles are found to have smaller reaction barriers by as much as 1.5 kcal/mol. The methods presented here have been implemented into the FE-ToolKit software package along with new methods for network-wide free energy analysis in drug discovery.
机译：我们使用基数B样条基重新发展了变分自由能分布（vFEP）方法，以扩展分析涉及三个或更多反应坐标的自由能表面（FES）的方法。我们还实现了基于多状态贝内特接受率（MBAR）方法的高维剖面评估软件，该方法通过对观测样本进行全局重新加权来构造无偏概率密度。MBAR方法利用了求解无约束加权直方图（UWHAM）/MBAR方程的快速算法，用凸函数的非线性优化代替联立方程的求解。我们利用基数B样条和多重二次径向基函数来获得任意高维的光滑、可微的MBAR轮廓。使用三个检查1D、2D和3D剖面的示例系统，比较了基数B样条vFEP和MBAR方法。这两种方法都很有用，结果几乎无法区分。当应用于周期性二维剖面时，vFEP方法比MBAR方法快150倍，但在评估无边界三维剖面时，MBAR方法比vFEP方法快4.5倍。与之前的比较一致，我们发现当伞形窗模拟之间的重叠减少时，vFEP方法产生了更好的FES。最后，利用3D、4D和6D图谱对锤头状核酶的结合反应机制进行了表征，发现高维图谱的反应屏障更小，高达1.5 kcal/mol。本文介绍的方法已与药物发现中的网络自由能分析新方法一起应用到FE ToolKit软件包中。

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