BAR-Based Multi-Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region,Advanced Theory and Simulations

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BAR-Based Multi-Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region
Advanced Theory and Simulations ( IF 2.9 ) Pub Date : 2021-09-08 , DOI: 10.1002/adts.202100185
Zhaoxi Sun ₁ , Zhirong Liu ₁

Affiliation

The indirect free energy simulation at quantum mechanics (QM)/ molecular mechanics (MM) levels provides a feasible alternative to direct QM/MM simulations. The main idea under the indirect method is constructing a thermodynamic cycle, exploring the configurational space under a cheaper but less accurate QM level, and performing an alchemical correction to obtain the thermodynamics under an accurate but computationally demanding QM level. In the authors' previous works, a multi-dimensional nonequilibrium free energy simulation framework was developed to obtain QM/MM free energy landscapes indirectly, where the QM theory is varied but the other details of the multi-scale treatment remain unchanged. In this work, the possibility of changing the region for electronic structure calculations in the multi-scale treatment is explored. Numerical tests are performed for the conformational change in a biologically relevant peptide in vacuo and in solution, and the QM region and QM level are varied simultaneously. Unidirectional and bidirectional equilibrium perturbations are also performed for comparison. The indirect estimates from the nonequilibrium perturbation framework are almost identical to the direct results, while the indirect equilibrium estimates show obvious deviations from the direct references. They further derive the acceleration ratio of the indirect scheme to understand when the indirect scheme prevails.

中文翻译：

基于 BAR 的多维非平衡拉动，用于间接构建 QM/MM 自由能景观：改变 QM 区域

量子力学 (QM)/分子力学 (MM) 级别的间接自由能模拟为直接 QM/MM 模拟提供了可行的替代方案。间接方法下的主要思想是构建热力学循环，在更便宜但精度较低的 QM 水平下探索构型空间，并进行炼金术校正以获得准确但计算要求高的 QM 水平下的热力学。在作者之前的工作中，开发了一个多维非平衡自由能模拟框架来间接获得 QM/MM 自由能景观，其中 QM 理论有所变化，但多尺度处理的其他细节保持不变。在这项工作中，探索了在多尺度处理中改变电子结构计算区域的可能性。对真空和溶液中生物相关肽的构象变化进行数值测试，同时改变 QM 区域和 QM 水平。还进行了单向和双向平衡扰动以进行比较。非均衡扰动框架的间接估计与直接结果几乎相同，而间接均衡估计与直接参考有明显的偏差。他们进一步推导出间接方案的加速比，以了解间接方案何时盛行。非均衡扰动框架的间接估计与直接结果几乎相同，而间接均衡估计与直接参考有明显的偏差。他们进一步推导出间接方案的加速比，以了解间接方案何时盛行。非均衡扰动框架的间接估计与直接结果几乎相同，而间接均衡估计与直接参考有明显的偏差。他们进一步推导出间接方案的加速比，以了解间接方案何时盛行。

更新日期：2021-10-04

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