We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.

A protocol for the ab initio crystal structure determination of powdered solids at natural isotopic abundance by combining solid-state NMR spectroscopy, crystal structure prediction, and DFT chemical shift calculations was evaluated to determine the crystal structures of four small drug molecules: cocaine, flutamide, flufenamic acid, and theophylline. For cocaine, flutamide and flufenamic acid, we find that the assigned 1 H isotropic chemical shifts provide sufficient discrimination to determine the correct structures from a set of predicted structures using the root-mean-square deviation (rmsd) between experimentally determined and calculated chemical shifts. In most cases unassigned shifts could not be used to determine the structures. This method requires no prior knowledge of the crystal structure, and was used to determine the correct crystal structure to within an atomic rmsd of less than 0.12 Å with respect to the known reference structure. For theophylline, the NMR spectra are too simple to allow for unambiguous structure selection.

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Computer modeling techniques were employed to investigate the adsorption of a selection of organic molecules to a series of monatomic growth steps of the major calcium carbonate polymorph calcite. Incorporation of the organic material by replacement of preadsorbed water at calcite {101 h4} surface features is calculated to be considerably exothermic for organic molecules containing carbonyl and hydroxy functional groups with adsorption energies at the growth steps ranging from about -30 to -140 kJ mol -1 . The calculated energies suggest that carboxylic acids, hydroxy aldehydes, or amides will be effective growth inhibitors through their strong adsorption to the growth steps, usually binding across the step to the terrace below, thereby blocking these sites to further attachment by calcium carbonate. Organic molecules containing only the amine functional group do not adsorb very strongly to the growth steps and thus will not be particularly effective in inhibiting crystal growth. On the stoichiometric steps, which are found in abundance on the experimental surface, hydroxy ethanal preferentially blocks the faster growing obtuse steps, which will slow calcite growth significantly. On the steps terminated by either calcium or carbonate groups, the adsorbates are found to attach preferentially to either the acute or the obtuse steps, which may lead to asymmetric growth and surface morphology. The results from this study suggest that computer simulations may provide a route to the identification or even design of particular organic additives for specific tailored crystal growth.

The computer-generation of the crystal structures of the α-amino acid valine is used as a challenging test of lattice energy modeling methods for crystal structure prediction of flexible polar organic molecules and, specifically, to examine the importance of molecular polarization on calculated relative energies. Total calculated crystal energies, which combine atom-atom model potential calculations of intermolecular interactions with density functional theory intramolecular energies, do not effectively distinguish the real (known) crystal structures from the rest of the low energy computer-generated alternatives when the molecular electrostatic models are derived from isolated molecule calculations. However, we find that introducing a simple model for the bulk crystalline environment when calculating the molecular energy and electron density distribution leads to important changes in relative total crystal energies and correctly distinguishes the observed crystal structures from the set of computer-generated possibilities. This study highlights the importance of polarization of the molecular charge distribution in crystal structure prediction calculations, especially for polar flexible molecules, and suggests a computationally inexpensive approach to include its effect in lattice energy calculations.

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