Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations
Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations
复制标题
炼金元动力学：在元动力学中添加炼金变量以增强自由能计算中的采样
DOI：
10.1021/acs.jctc.2c01258
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发表时间：
2023
影响因子：
5.5
通讯作者：
Shirts, Michael R.
中科院分区：
文献类型：
--
作者：
Hsu, Wei-Tse;Piomponi, Valerio;Merz, Pascal T.;Bussi, Giovanni;Shirts, Michael R.
执行炼金术转换，其中一个分子系统被非物理地改变为另一个系统，是一种流行的方法，用于执行与各种生物物理过程相关的自由能计算，例如蛋白质-配体结合或分子在环境之间的转移。虽然炼金术中间状态的采样在任一并行（例如，汉密尔顿复制交换）或串行方式（例如，扩展的系综）可以桥接感兴趣的两个端态之间的构型空间中的高概率区域，但炼金术方法可能在构型空间中最重要的慢自由度在很大程度上与炼金术变量正交的情况下失败，或者如果系统被困在在构型空间和炼金术空间两者中延伸的深盆中。为了缓解这些问题，我们建议使用炼金术变量作为一个额外的维度在元分析，使其有可能既采样集体变量，并同时提高采样自由能计算。在这项研究中，我们验证了我们的实施“炼金术metadaptics”在PLUMED与测试系统和炼金术的过程与不同的复杂性和维度的集体变量空间，包括之间的相互转换的扭转亚稳态的玩具系统和甲基化的核苷都在孤立的形式和双链体。我们表明，多维炼金术元可以解决上述挑战，并通过引入配置集体变量进一步加速采样。该方法可以与PLUMED中实现的其他基于元数据的算法相结合。必要的PLUMED代码更改已经在PLUMED 2.8中发布以供一般使用。
Performing alchemical transformations, in which one molecular system is nonphysically changed to another system, is a popular approach adopted in performing free energy calculations associated with various biophysical processes, such as protein–ligand binding or the transfer of a molecule between environments. While the sampling of alchemical intermediate states in either parallel (e.g., Hamiltonian replica exchange) or serial manner (e.g., expanded ensemble) can bridge the high-probability regions in the configurational space between two end states of interest, alchemical methods can fail in scenarios where the most important slow degrees of freedom in the configurational space are, in large part, orthogonal to the alchemical variable, or if the system gets trapped in a deep basin extending in both the configurational and alchemical space. To alleviate these issues, we propose to use alchemical variables as an additional dimension in metadynamics, making it possible to both sample collective variables and to enhance sampling in free energy calculations simultaneously. In this study, we validate our implementation of “alchemical metadynamics” in PLUMED with test systems and alchemical processes with varying complexities and dimensionalities of collective variable space, including the interconversion between the torsional metastable states of a toy system and the methylation of a nucleoside both in the isolated form and in a duplex. We show that multidimensional alchemical metadynamics can address the challenges mentioned above and further accelerate sampling by introducing configurational collective variables. The method can trivially be combined with other metadynamics-based algorithms implemented in PLUMED. The necessary PLUMED code changes have already been released for general use in PLUMED 2.8.