Fast energy minimization of the CCDC drug-subset structures by molecule-in-cluster computations allows independent structure validation and model completion

Abstract

Optimizing structures with computations on clusters of molecules permits generation of structure-specific restraints for refinement. Equally importantly, retrospective structure validation and addition of hydrogen atoms consistent with quantum chemistry is...

On modelling disordered crystal structures through restraints from molecule-in-cluster computations, and distinguishing static and dynamic disorder

“…Crystallographic ONIOM (Svensson et al, 1996) MO/MO or QM/MM cluster computations, and those where the same level of theory is used throughout, have in common that molecules in the ASU are expanded to generate a cluster of molecules using space-group symmetry. This is why I jointly call them molecule-in-cluster computations (Dittrich et al, 2020a) here. ONIOM cluster computations were first used in SC-XRD to calculate reference values for the internal part of atomic displacements of hydrogen atoms (Whitten & Spackman, 2006).…”

“…All these computations have in common that a cluster, which consists of molecules or ions in proximity to a central system, reproduces the crystal environment. The advent of the tight-binding semi-empirical GFN2-xTB (Bannwarth et al, 2019) approach induces new momentum to cluster computations because of the considerable speed up (Dittrich et al, 2020a). What took days (hours) before takes hours (minutes) now, depending on the computer system.…”

“…These developments open up several new applications of molecule-in-cluster computations, e.g. structure validation (Dittrich et al, 2020a), modelling disorder structures with restraints (studied here), complementing or replacing Rietveld refinement (Rietveld, 1969) in structure solution from powder X-ray diffraction (David & Shankland, 2008), benchmarking theoretical computations with highquality experimental diffraction data and investigating cocrystal structures, to name just a few.…”

“…Five disordered compounds from the CCDC drug subset (Bryant et al, 2019) were initially selected for study. Computations performed in our earlier study (Dittrich et al, 2020a) on the drug subset were partly relied upon for these structures. Their diffraction data were deposited alongside publications in the journals of Acta Crystallographica sections C and E. For two further examples, propionamide (Fabbiani et al, 2014) and DL-arginine monohydrate (Kingsford-Adaboh et al, 2002) data were collected by the author.…”

“…It will also be reported how to improve the technical modelling procedure of disordered crystal structures by introducing restraints (Watkin, 1994) from molecule-in-cluster geometry optimizations (Dittrich et al, 2020a) of archetype structures (Dittrich et al, 2020b). Initial coordinates of archetype 1 structures can be extracted from disordered experimental structures and then optimized.…”