Nuclear-Electronic Orbital QM/MM Approach: Geometry Optimizations and Molecular Dynamics

Mathew Chow, Eleftherios Lambros, Xiaosong Li, Sharon Hammes-Schiffer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Hybrid quantum mechanical/molecular mechanical (QM/MM) methods allow simulations of chemical reactions in atomistic solvent and heterogeneous environments such as proteins. Herein, the nuclear-electronic orbital (NEO) QM/MM approach is introduced to enable the quantization of specified nuclei, typically protons, in the QM region using a method such as NEO-density functional theory (NEO-DFT). This approach includes proton delocalization, polarization, anharmonicity, and zero-point energy in geometry optimizations and dynamics. Expressions for the energies and analytical gradients associated with the NEO-QM/MM method, as well as the previously developed polarizable continuum model (NEO-PCM), are provided. Geometry optimizations of small organic molecules hydrogen bonded to water in either dielectric continuum solvent or explicit atomistic solvent illustrate that aqueous solvation can strengthen hydrogen-bonding interactions for the systems studied, as indicated by shorter intermolecular distances at the hydrogen-bond interface. We then performed a real-time direct dynamics simulation of a phenol molecule in explicit water using the NEO-QM/MM method. These developments and initial examples provide the foundation for future studies of nuclear-electronic quantum dynamics in complex chemical and biological environments.

Original languageEnglish (US)
Pages (from-to)3839-3848
Number of pages10
JournalJournal of Chemical Theory and Computation
Issue number13
StatePublished - Jul 11 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Computer Science Applications
  • Physical and Theoretical Chemistry


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