Quantum refinement in real and reciprocal space using the Phenix and ORCA software

Summary, in English

X-ray and neutron crystallography, as well as cryogenic electron microscopy (cryo-EM), are the most common methods to obtain atomic structures of biological macromolecules. A feature they all have in common is that, at typical resolutions, the experimental data need to be supplemented by empirical restraints, ensuring that the final structure is chemically reasonable. The restraints are accurate for amino acids and nucleic acids, but often less accurate for substrates, inhibitors, small-molecule ligands and metal sites, for which experimental data are scarce or empirical potentials are harder to formulate. This can be solved using quantum mechanical calculations for a small but interesting part of the structure. Such an approach, called quantum refinement, has been shown to improve structures locally, allow the determination of the protonation and oxidation states of ligands and metals, and discriminate between different interpretations of the structure. Here, we present a new implementation of quantum refinement interfacing the widely used structure-refinement software Phenix and the freely available quantum mechanical software ORCA. Through application to manganese superoxide dismutase and V- and Fe-nitrogenase, we show that the approach works effectively for X-ray and neutron crystal structures, that old results can be reproduced and structural discrimination can be performed. We discuss how the weight factor between the experimental data and the empirical restraints should be selected and how quantum mechanical quality measures such as strain energies should be calculated. We also present an application of quantum refinement to cryo-EM data for particulate methane monooxygenase and show that this may be the method of choice for metal sites in such structures because no accurate empirical restraints are currently available for metals.

• Author: Kristoffer J.M. Lundgren; Octav Caldararu; Esko Oksanen; Ulf Ryde
• Department/s: Computational Chemistry; eSSENCE: The e-Science Collaboration
• Publishing year: 2024-11-01
• Language: English
• Pages: 921-937
• Publication/Series: IUCrJ
• Volume: 11
• Issue: Pt 6
• Links: http://dx.doi.org/10.1107/S2052252524008406
• Document type: Journal article
• Publisher: International Union of Crystallography
• Topic: Theoretical Chemistry (including Computational Chemistry)
• Keywords: cryo-EM; Fe-nitrogenase; Mn superoxide dismutase; neutron crystallography; particulate methane monooxygenase; QM/MM; quantum refinement; V-nitrogenase; X-ray crystallography
• Status: Published
• ISBN/ISSN/Other: ISSN: 2052-2525