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炼金术元动力学:在元动力学中添加炼金术变量以增强自由能计算中的采样

Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations.

作者信息

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

机构信息

Department of Chemical and Biological Engineering, University of Colorado at Boulder, Boulder, Colorado 80305, United States.

Scuola Internazionale Superiore di Studi Avanzati, via Bonomea 265, 34136 Trieste, Italy.

出版信息

J Chem Theory Comput. 2023 Mar 28;19(6):1805-1817. doi: 10.1021/acs.jctc.2c01258. Epub 2023 Feb 28.


DOI:10.1021/acs.jctc.2c01258
PMID:36853624
Abstract

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.

摘要

进行炼金术变换(即将一个分子系统非物理地转变为另一个系统)是在执行与各种生物物理过程相关的自由能计算时采用的一种流行方法,这些生物物理过程包括蛋白质 - 配体结合或分子在不同环境之间的转移。虽然以并行方式(例如哈密顿副本交换)或串行方式(例如扩展系综)对炼金术中间态进行采样可以跨越感兴趣的两个终态在构型空间中的高概率区域,但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,或者如果系统陷入构型空间和炼金术空间中都延伸的深势阱时,炼金术方法可能会失效。为了缓解这些问题,我们建议在元动力学中使用炼金术变量作为额外维度,从而有可能在自由能计算中同时对集体变量进行采样并增强采样。在本研究中,我们使用具有不同复杂度和集体变量空间维度的测试系统和炼金术过程,包括一个玩具系统的扭转亚稳态之间的相互转换以及孤立形式和双链体形式下核苷的甲基化,来验证我们在PLUMED中实现的“炼金术元动力学”。我们表明,多维炼金术元动力学可以应对上述挑战,并通过引入构型集体变量进一步加速采样。该方法可以很容易地与PLUMED中实现的其他基于元动力学的算法相结合。必要的PLUMED代码更改已经发布,可在PLUMED 2.8中通用。

相似文献

[1]
Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations.

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[7]
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[8]
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引用本文的文献

[1]
Simultaneous Construction of Free Energy Surfaces via Multisite λ Dynamics and Umbrella Sampling.

J Chem Theory Comput. 2025-9-9

[2]
Multiple Topology Replica Exchange of Expanded Ensembles for Multidimensional Alchemical Calculations.

J Chem Theory Comput. 2025-1-14

[3]
Automated Adaptive Absolute Binding Free Energy Calculations.

J Chem Theory Comput. 2024-9-10

[4]
Computational studies on the catalytic potential of the double active site for enzyme engineering.

Sci Rep. 2024-8-2

[5]
Replica Exchange of Expanded Ensembles: A Generalized Ensemble Approach with Enhanced Flexibility and Parallelizability.

J Chem Theory Comput. 2024-7-23

[6]
Current State of Open Source Force Fields in Protein-Ligand Binding Affinity Predictions.

J Chem Inf Model. 2024-7-8

[7]
Expanded ensemble predictions of absolute binding free energies in the SAMPL9 host-guest challenge.

Phys Chem Chem Phys. 2023-12-6

[8]
OneOPES, a Combined Enhanced Sampling Method to Rule Them All.

J Chem Theory Comput. 2023-9-12

[9]
Identifying and Overcoming the Sampling Challenges in Relative Binding Free Energy Calculations of a Model Protein:Protein Complex.

J Chem Theory Comput. 2023-8-8

[10]
Identifying and overcoming the sampling challenges in relative binding free energy calculations of a model protein:protein complex.

bioRxiv. 2023-6-21

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