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Accelerated Computation of Free Energy Profile at Ab Initio Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference-Potential. 4. Adaptive QM/MM

revised on 02.02.2021, 10:03 and posted on 03.02.2021, 08:57 by Jia-Ning Wang, Wei Liu, Pengfei Li, Yan Mo, Wenxin Hu, Jun Zheng, Xiaoliang Pan, Yihan Shao, Ye Mei
Although Quantum Mechanical/Molecular Mechanics (QM/MM) methods are now routinely applied to the studies of chemical reactions in condensed phases and enzymatic reactions, they may experience technical difficulties when the reactive region is varying over time. For instance, when the solvent molecules are directly participating in the reaction, the exchange of water molecules between the QM and MM regions may occur on a time scale comparable to the reaction time. To cope with this situation, several adaptive QM/MM schemes have been proposed. However, these methods either add significantly to the computational cost or introduce artificial restraints to the system. In this work, we developed a novel adaptive QM/MM scheme and applied it to a study of a nucleophilic addition reaction. In this scheme, the configuration sampling was performed with a small QM region (without solvent molecules), and the thermodynamic properties under another potential energy function with a larger QM region (with a certain number of solvent molecules and/or different levels of QM theory) are computed via extrapolation using the reference-potential method. Our simulation results show that this adaptive QM/MM scheme is numerically stable, at least for the case studied in this work. Furthermore, this method also offers an inexpensive way to examine the convergence of the QM/MM calculation with respect to the size of the QM region.


National Natural Science Foundation of China

Fundamental Research Funds for the Central Universities

National Institutes of Health


Email Address of Submitting Author


East China Normal University



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest