Dittrich, Birger, Breznikar, Rok, Santarossa, Gianluca, Pamela, Whitfield and Moebitz, Henrik (2025) Benchmarking quantum chemical methods with X-ray structures via structure-specific bond-distance/angle restraints. IUCrJ.

Abstract

There is a need for fast, efficient, and accurate solid-state structure optimization for property prediction in the pharmaceutical industry. Optimizing structures of organic non-polymeric molecules including salts, solvates and cocrystals by efficient “molecule-in-cluster” (MIC) computations (Dittrich, Chan, et al., 2020) is therefore further investigated. The accuracy in reproducing experimental structure by semiempirical quantum mechanical (SQM) or quantum mechanical (QM) methods is evaluated by comparison to 22 very low-temperature high-resolution small-molecule crystal structures after aspherical-atom refinement. MIC GFN2-XTB, QM:MM (molecular mechanics), MO:MO (molecular orbital) were assessed and compared to full-periodic computations. Individual differences in bond distances between experiment and theory frequently exceed 0.005 Å. Since a bond-specific statistical analysis would require a much larger data set of structures, evaluating QM method performance was achieved by enforcing computed restraints in crystallographic least-squares refinements, followed by comparing the magnitude of root mean square Cartesian displacements (RMSCD) of computed and experimental structures. Analysis shows that MIC computations are a computationally efficient and accurate tool for solid-state structure optimization. Disagreements between experiment and high-level theory raise questions about their origin. Concerning practical application of structure-specific restraints, augmenting structural quality from comparably inaccurate experimental structures, e.g. from low-resolution refinement, 3D electron or powder diffraction, becomes possible. Augmenting such experimental results can then provide similar structural quality than low-temperature high-resolution single-crystal X-ray diffraction. For these applications, further improving efficiency and accuracy of optimization for providing restraints remains desirable.

Item Type:	Article
Keywords:	Quantum crystallography, DFT benchmarking, crystal structures, accurate structure-specific restraints
Date Deposited:	02 Jul 2025 00:46
Last Modified:	02 Jul 2025 00:46
URI:	https://oak.novartis.com/id/eprint/55296