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

Abstract

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.

Keywords: Cambridge Structural Database; crystal structure prediction; lattice energies; polymorphism.

Figure 1

Experimental crystal structure of (XXII); C atoms are in grey, N in blue and S in yellow.

Figure 2

Molecular conformations found in forms A–D of (XXIII), overlaid onto the fenemate group of the molecule; form A is in blue, form B in grey, form C molecule 1 is in red, form C molecule 2 in purple and form D in orange. H atoms are omitted for clarity.

Figure 3

Crystal structures of (a) form A and (b) form D of (XXIII), showing the similar layers found in the two structures. H atoms are omitted for clarity.

Figure 4

Experimental crystal structure of (XXIV) showing both the hydrogen bonds of the asymmetric unit and the unit cell; C atoms are in grey, H in white, O in red, N in blue, S in yellow and Cl in green.

Figure 5

Experimental crystal structure of (XXV) at 300 K, showing the asymmetric unit and the unit cell; C atoms are in grey, H in white, O in red and N in blue. The proton is shown as originally refined at 300 K, attached to the carboxylic acid. Close analysis of the data and further data collected at 100 K suggest that a disordered structure with the H atom occupying two sites is more representative.

Figure 6

Experimental crystal structure of (XXVI), showing the molecular conformation and the unit cell, with hydrogen bonds shown by blue lines; C atoms are in grey, H in white, O in red, Cl in green and N in blue.

Figure 7

Two example overlays of the experimental crystal structure of (XXII) with predicted structures of (a) Tkatchenko et al. with an RMSD of 0.166 Å, and (b) Obata & Goto with an RMSD of 0.808 Å. The predicted structures are shown in green for clarity. With the smaller RMSD in (a) the two structures are difficult to distinguish visually, while for the larger RMSD in (b) the predicted and experimental molecules are clearly offset.