Report on the sixth blind test of organic crystal structure prediction methods.

The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and `best practices' for performing CSP calculations. All of the targets, apart from a single potentially disordered Z' = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms.

Towards crystal structure prediction of complex organic compounds--a report on the fifth blind test.

Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories - a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.

Significant progress in predicting the crystal structures of small organic molecules--a report on the fourth blind test.

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.

Comparing hypothetical structures generated in the third Cambridge blind test of crystal structure prediction.

In the third Cambridge blind test of crystal structure prediction, participants submitted extended lists of up to 100 hypothetical structures. In this paper these lists are analyzed for the two small semi-rigid molecules, hydantoin and azetidine, by performing a new energy minimization using an accurate force field, and grouping these newly minimized structures into clusters of equivalent structures. Many participants found the same low-energy structures, but no list appeared to be complete even for the structures with one independent molecule in the asymmetric unit. This may well be due to the fact that a cutoff at even 100 structures cannot ensure the presence of a structure that has a relatively high ranking in another force field. Moreover, some structures should have possibly been discarded because they correspond to transition states rather than true energy minima. The r.m.s. deviation between energies in corresponding clusters was calculated to compare the reported relative crystal energies for each pair of participants. Some groups of force fields show a reasonably good correspondence, yet the order of magnitude of their discrepancies is comparable to the energy differences between, say, the first ten structures of lowest energy. Therefore, even if we assume that energy is a sufficient criterion, it is not surprising that crystal structure predictions are still inconsistent and unreliable.

Crystal structure prediction of small organic molecules: a second blind test.

The first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy. A maximum of three predictions were allowed per molecule. The results showed two correct predictions for the first molecule, four for the second molecule and none for the third molecule (which had torsional flexibility). The correct structure was often present in the sorted low-energy lists from the participants but at a ranking position greater than three. The use of non-indexed powder diffraction data was investigated in a secondary test, after completion of the ab initio submissions. Although no one method can be said to be completely reliable, this workshop gives an objective measure of the success and failure of current methodologies.

Crystal structure predictions using five space groups with two independent molecules. The case of small organic acids.

Crystal structure generations with two independent molecules have been performed for a series of carboxylic acids, using a slightly modified version of the OPLS force field. It was found that in this way the experimental structures with one independent molecule were produced as special cases, except for the molecules with four or more internal degrees of freedom. This work shows that a search with two independent molecules in only five space groups, although costly in computer power, can automatically also find structures with one independent molecule in many supergroups. Considering the observed abundances of structural classes, such a search should cover more than 95% of the possible homomolecular crystal structures.

Upack program package for crystal structure prediction: Force fields and crystal structure generation for small carbohydrate molecules.

The Upack program package for crystal structure generation was used to build hypothetical crystal structures for 32 pyranoses and 24 polyalcohols. A subset of these was used to compare six force fields in their ability to reproduce the experimentally observed structures, preferably with low energies and high rankings with respect to the structure with lowest energy. One of these force fields, Unitat, was derived from Gromos87 by adjusting some parameters to obtain a better geometric description of these crystal structures. This united-atom force field and the all-atom Opls force field performed best, and were used in the crystal structure generation for the full set of compounds. For these carbohydrates, hundreds of hypothetical polymorphic structures are generated in an energy window of about 25 kJ/mol. On average, the experimental structures had reasonable energies and rankings. These lists are good starting points for more sophisticated calculations, and can be used for structure determination by powder diffraction methods. In a few cases, serious doubt was raised concerning the hydrogen-bond network reported in the literature, for which more plausible alternatives appear to exist. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 799-812, 1999.