Using the Quantum Interface in Phenix to improve macromolecular model and ligand structures Article Swipe

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Nigel W. Moriarty , Jonathan E. Moussa , Paul D. Adams · YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.1063/4.0000364

Quantum Mechanical methods provide geometries and energies of molecules using just the atomic and electronic positions. Being independent of the experimental data, they provide complementary information. Furthermore, allowing the experimental and QM methods to share information leads to better results. The Quantum Interface (QI) in Phenix (Liebschner et al., 2019) provides close integration with MOPAC (Moussa & Stewart, 2024) allowing the calculation of in situ restraints for drug candidates. Known as QM Restraints (QMR) (Liebschner et al., 2023), this method will provide protein binding pocket specific restraints during a refinement or in a stand-alone program. Another QI procedure is a novel approach for predicting histidine protonation states using QM methods. Historically, determining histidine protonation has been challenging due to limited resolution in X-ray crystallography and the inherent difficulty in detecting hydrogen atoms. Previous methods relied on empirical or geometric models, which provided some insights but had limitations. The proposed method, Quantum Mechanical Flipping (QMF) (Moriarty et al., In review), employs quantum mechanical calculations to predict protonation states based on the molecular environment. This approach considers all possible configurations of histidine protonation and assesses their feasibility by minimising geometry and energy calculations. QMF accounts for factors such as hydrogen bonding and molecular interactions providing a more accurate prediction of the most likely protonation state particularly in the binding pocket. The study demonstrates the effectiveness of QMF through comparisons with existing methods and validation using high- resolution protein structures. Results show that QMF can accurately predict histidine protonation states, even in cases with limited experimental data. Additionally, QMF's versatility allows it to be applied to various macromolecular environments, including ligand interactions and non-standard amino acids. Other applications of QI include metal coordination and ligand strain energies, both of which are being pursued.

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article

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en

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https://doi.org/10.1063/4.0000364

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gold

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2

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10

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https://openalex.org/W4409325174

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https://openalex.org/W4409325174

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https://doi.org/10.1063/4.0000364

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Using the Quantum Interface in Phenix to improve macromolecular model and ligand structures

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article

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en

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2025

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2025-03-01

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Nigel W. Moriarty, Jonathan E. Moussa, Paul D. Adams

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https://doi.org/10.1063/4.0000364

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gold

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https://doi.org/10.1063/4.0000364

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Interface (matter), Ligand (biochemistry), Quantum, Macromolecule, Quantum chemical, Computer science, Physics, Chemical physics, Chemistry, Molecule, Quantum mechanics, Gibbs isotherm, Receptor, Biochemistry

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2

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10

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