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Abstract Quantum mechanics/molecular mechanics (QM/MM) simulations are a popular approach to study various features of large systems. A common application of QM/MM calculations is in the investigation of reaction mechanisms in condensed‐phase and biological systems. The combination of QM and MM methods to represent a system gives rise to several challenges that need to be addressed. The increase in computational speed has allowed the expanded use of more complicated and accurate methods for both QM and MM simulations. Here, we review some approaches that address several common challenges encountered in QM/MM simulations with advanced polarizable potentials, from methods to account for boundary across covalent bonds and long‐range effects, to polarization and advanced embedding potentials. This article is categorized under:Electronic Structure Theory > Combined QM/MM MethodsMolecular and Statistical Mechanics > Molecular InteractionsSoftware > Simulation Methods
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This content will become publicly available on December 1, 2025
Constrained nuclear-electronic orbital QM/MM approach for simulating complex systems with quantum nuclear delocalization effects incorporated
The hybrid quantum mechanics/molecular mechanics (QM/MM) approach, which combines the accuracy of QM methods with the efficiency of MM methods, is widely used in the study of complex systems. However, past QM/MM implementations often neglect or face challenges in addressing nuclear quantum effects, despite their crucial role in many key chemical and biological processes. Recently, our group developed the constrained nuclear-electronic orbital (CNEO) theory, a cost-efficient approach that accurately addresses nuclear quantum effects, especially quantum nuclear delocalization effects. In this work, we integrate CNEO with the QM/MM approach through the electrostatic embedding scheme and apply the resulting CNEO QM/MM to two hydrogen-bonded complexes. We find that both solvation effects and nuclear quantum effects significantly impact hydrogen bond structures and dynamics. Notably, in the glutamic acid–glutamate complex, which mimics a common low barrier hydrogen bond in biological systems, CNEO QM/MM accurately predicts nearly equal proton sharing between the two residues. With an accurate description of both quantum nuclear delocalization effects and environmental effects, CNEO QM/MM is a promising new approach for simulating complex chemical and biological systems.
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- Award ID(s):
- 2238473
- PAR ID:
- 10557631
- Publisher / Repository:
- American Institute of Physics
- Date Published:
- Journal Name:
- Chemical Physics Reviews
- Volume:
- 5
- Issue:
- 4
- ISSN:
- 2688-4070
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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