In situ ligand restraints from quantum‐mechanical methods. Issue 2 (20th January 2023)

• Record Type: Journal Article
• Authors: Liebschner, Dorothee; Moriarty, Nigel W.; Poon, Billy K.; Adams, Paul D.
• Is Part Of: Acta crystallographica. Volume 79:Issue 2(2023)
• Page Start: 100
• Page End: 110
• Publication Date: 2023-01-20
• Subjects: macromolecular crystallography -- ligand restraints -- refinement -- quantum mechanics -- Quantum Mechanical Restraints; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; Molecular biology -- Periodicals; Molecular structure -- Periodicals; Biomolecules -- Structure -- Periodicals; Cytology -- Periodicals; Biomolecules -- Structure; Crystallography; Cytology; Molecular biology; Molecular structure; X-ray crystallography; Periodicals; 548
• DOI: 10.1107/S2059798323000025
• Languages: English
• ISSNs: 2059-7983

Abstract

Abstract : In situ quantum‐mechanical optimization of ligand structures provides accurate ligand restraints for macromolecular refinement. Abstract : In macromolecular crystallographic structure refinement, ligands present challenges for the generation of geometric restraints due to their large chemical variability, their possible novel nature and their specific interaction with the binding pocket of the protein. Quantum‐mechanical approaches are useful for providing accurate ligand geometries, but can be plagued by the number of minima in flexible molecules. In an effort to avoid these issues, the Quantum Mechanical Restraints (QMR) procedure optimizes the ligand geometry in situ, thus accounting for the influence of the macromolecule on the local energy minima of the ligand. The optimized ligand geometry is used to generate target values for geometric restraints during the crystallographic refinement. As demonstrated using a sample of >2330 ligand instances in >1700 protein–ligand models, QMR restraints generally result in lower deviations from the target stereochemistry compared with conventionally generated restraints. In particular, the QMR approach provides accurate torsion restraints for ligands and other entities.