Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations.
Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations.
复制标题
使用选择性应用加速分子动力学来增强自由能计算。
DOI：
10.1021/ct100322t
复制
发表时间：
2010
影响因子：
5.5
通讯作者：
McCammon,JAndrew
中科院分区：
文献类型：
--
作者：
Wereszczynski,Jeff;McCammon,JAndrew
加速分子动力学（aMD）已被证明可以增强相对于经典分子动力学的构象空间采样;然而，aMD轨迹的指数重新加权，这是计算与经典系统相关的自由能所必需的，通常是有问题的，特别是对于大于小多肽的系统。在这里，我们提出了一种方法，只加速最相关的采样的自由度，从而减少总加速度添加到系统和提高计算的合奏平均值，我们termselective aMD的收敛。它的应用突出在两个生物分子的情况下。首先，模型系统丙氨酸二肽模拟与经典MD，所有二面角的aMD，和选择性aMD，这些结果相比，无限的采样限制与metadaptics计算。我们发现，这两种形式的aMD增强收敛的基本自由能景观5倍，相对于经典MD，然而，选择性aMD可以产生改进的统计，由于改进的重新加权。然后，我们专注于计算奥司他韦在神经氨酸酶的活性位点的解耦的自由能的药学相关的情况下。结果表明，选择性aMD大大降低了成本，这种炼金术的自由能转换，而所有二面角aMD产生不可靠的自由能估计。
Accelerated molecular dynamics (aMD) has been shown to enhance conformational space sampling relative to classical molecular dynamics; however, the exponential reweighting of aMD trajectories, which is necessary for the calculation of free energies relating to the classical system, is oftentimes problematic, especially for systems larger than small poly peptides. Here, we propose a method of accelerating only the degrees of freedom most pertinent to sampling, thereby reducing the total acceleration added to the system and improving the convergence of calculated ensemble averages, which we termselective aMD. Its application is highlighted in two biomolecular cases. First, the model system alanine dipeptide is simulated with classical MD, all-dihedral aMD, and selective aMD, and these results are compared to the infinite sampling limit as calculated with metadynamics. We show that both forms of aMD enhance the convergence of the underlying free energy landscape by 5-fold relative to classical MD; however, selective aMD can produce improved statistics over all-dihedral aMD due to the improved reweighting. Then we focus on the pharmaceutically relevant case of computing the free energy of the decoupling of oseltamivir in the active site of neuraminidase. Results show that selective aMD greatly reduces the cost of this alchemical free energy transformation, whereas all-dihedral aMD produces unreliable free energy estimates.