Efficient Handling of Molecular Flexibility in Lattice Energy Minimization of Organic Crystals.

This paper presents a novel algorithm, CrystalOptimizer, for the minimization of the lattice energy of crystals formed by flexible molecules. The algorithm employs isolated-molecule quantum mechanical (QM) calculations of the intramolecular energy and conformation-dependent atomic multipoles in the course of the lattice energy minimization. The algorithm eliminates the need to perform QM calculations at each iteration of the minimization by using Local Approximate Models (LAMs), with a minimal impact on accuracy. Additional computational efficiencies are achieved by storing QM-derived components of the lattice energy model in a database and reusing them in subsequent calculations whenever possible. This makes the approach particularly well suited to applications that involve a sequence of lattice energy evaluations, such as crystal structure prediction. The algorithm is capable of handling efficiently complex systems with considerable conformational flexibility. The paper presents examples of the algorithm's application ranging from single-component crystals to cocrystals and salts of flexible molecules with tens of intramolecular degrees of freedom whose optimal values are determined by the interplay of conformational strain and packing forces. For any given molecule, the degree of flexibility to be considered can vary from a few torsional angles to relaxation of the entire set of torsion angles, bond angles, and bond lengths present in the molecule.

Tunable recognition of the steroid alpha-face by adjacent pi-electron density.

We report a previously unknown recognition motif between the alpha-face of the steroid hydrocarbon backbone and pi-electron-rich aromatic substrates. Our study is based on a systematic and comparative analysis of the solid-state complexation of four steroids with 24 aromatic molecules. By using the solid state as a medium for complexation, we circumvent solubility and solvent competition problems that are inherent to the liquid phase. Characterization is performed using powder and single crystal X-ray diffraction, infrared solid-state spectroscopy and is complemented by a comprehensive cocrystal structure prediction methodology that surpasses earlier computational approaches in terms of realism and complexity. Our combined experimental and theoretical approach reveals that the alpha...pi stacking is of electrostatic origin and is highly dependent on the steroid backbone's unsaturated and conjugated character. We demonstrate that the alpha...pi stacking interaction can drive the assembly of molecules, in particular progesterone, into solid-state complexes without the need for additional strong interactions. It results in a marked difference in the solid-state complexation propensities of different steroids with aromatic molecules, suggesting a strong dependence of the steroid-binding affinity and even physicochemical properties on the steroid's A-ring structure. Hence, the hydrocarbon part of the steroid is a potentially important variable in structure-activity relationships for establishing the binding and signaling properties of steroids, and in the manufacture of pharmaceutical cocrystals.

A third blind test of crystal structure prediction.

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.