论文标题

将炼金术变量添加到元动力学中,以增强自由能计算中的采样

Adding alchemical variables to metadynamics to enhance sampling in free energy calculations

论文作者

Hsu, Wei-Tse, Piomponi, Valerio, Merz, Pascal T., Bussi, Giovanni, Shirts, Michael R.

论文摘要

进行炼金术转化,其中一个分子系统非物理变为另一个系统,是一种流行的方法,它在执行与各种生物物理过程相关的自由能计算中采用了一种流行的方法,例如蛋白质 - 配体结合或环境之间的分子传递。虽然炼金术中间状态在平行(例如哈密顿复制交换)或串行方式(例如,扩展的合奏)可以弥合高概率的两个端口状态之间的高概率区域,但炼金学方法可以在各种情况下在各个方景中获得自由的较大偏移速度,如果是在大型系统中,大型偏离的偏移程度可能会在大型系统中逐渐变化。被困在构型和炼金术空间中延伸的深层盆地中。 为了减轻这些问题,我们建议将炼金术变量用作元动力学的附加维度,从而增强了采样集体变量并增强自由能计算中采样的能力。在这项研究中,我们验证了我们在测试系统和炼金术过程中的实施,具有不同的复杂性和集体可变空间的尺寸,包括玩具系统的扭转稳定状态以及隔离形式的核苷的甲基化状态之间的互转换。我们表明,多维炼金术元动力学可以解决上述挑战,并通过引入配置集体变量进一步加速采样。该方法可以与羽羽中实现的其他基于元动力学的算法合并。必要的羽毛代码更改已经发布,以供羽毛2.8中使用。

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, augmenting the ability both to sample collective variables and to enhance sampling in free energy calculations. In this study, we validate our implementation of alchemical metadynamics in PLUMED with test systems and alchemical processes with varying complexities and dimensions 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 multi-dimensional 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.

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