Details of Grant 

EPSRC Reference:	EP/C012127/1
Title:	Computational Prediction of Molecular Crystal Structures: Dynamics of Molecules in Crystals and Improved Energy Models for Pharmaceutical Molecules
Principal Investigator:	Day, Professor GM
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Chemistry
Organisation:	University of Cambridge
Scheme:	Advanced Fellowship (Pre-FEC)
Starts:	01 October 2005	Ends:	30 September 2010	Value (£):	215,639
EPSRC Research Topic Classifications:	Chemical Structure
EPSRC Industrial Sector Classifications:	No relevance to Underpinning Sectors
Related Grants:
Panel History:	Panel Date Panel Name Outcome 13 Apr 2005 Chemistry Fellowships Interview Panel Deferred 16 Mar 2005 Chemistry Fellowships Sift Panel 2005 Deferred
Summary on Grant Application Form
Molecules with useful properties, such as drugs, pigments or explosives, are usually used or stored in the form of crystals. Crystals of molecules are like 3-dimensional jigsaw puzzles, but built with pieces that don't quite fit - there are always gaps between molecules and much of a crystal is empty space. Because the molecules don't fit tightly, they usually have many options for how they arrange in the crystal. The structure that actually occurs is determined by a balance of effects. In fact, sometimes these are so evenly balanced between several possibilities that a molecule will crystallise in several structures. When more than one crystal structure is observed, the molecule is called polymorphic; the crystal structures are polymorphs.Because of the importance of crystals and the possibility of polymorphs, it would be very useful to be able to predict the structure of a crystal, starting from just a sketch of the molecule. Over the past ten years or so, computers have become powerful enough to study all of the possible ways of packing molecules into crystals. As a starting point, we normally consider the energy of a crystal of motionless molecules and assume that the crystal with the best possible energy is most likely to be observed. For a small molecule, we can generate tens of thousands of possible crystal structures in less than a week and compare the energies of all of these possibilities. Normally, tens or even hundreds of possibilities are found with acceptable energies and the preferred crystal may be favoured by much less than 1 kJ/mol - a tiny amount of energy. An added complication is that the motions (vibrations, etc) of molecules in the possible structures are different and will contribute varying amounts of energy to the different structures. With the small energy differences in the static energy calculations, these dynamic effects could reorder the predicted crystal structures. Therefore, what are needed are very accurate methods of calculating the energies of possible crystals and methods for studying the motion of molecules in the possible structures. Energies can now be calculated quite reliably for crystals of small molecules, where the shape of the molecule is not distorted by it being in the crystal. However, many molecules of interest are less rigid, so can distort their shape to fit into the crystal and optimise contacts with other molecules. This distortion costs energy, so the overall differences in energy between crystals are then the total of the molecule's energy and the interactions between molecules. Current methods of calculating this total energy have not been generally successful in calculating these energy differences for flexible molecules with the accuracy that is required. The methods that have been used to improve the calculations for small molecules are not easily extended to larger molecules. One part of my proposed research is to develop the tools for calculating accurate energy differences between crystals of flexible molecules and applying these tools to the prediction of crystal structures for flexible pharmaceutical molecules. The second part of my research is to assess and develop methods for studying the motions of molecules in crystals. Until now, there have been limited studies of the dynamics in organic molecular crystals, especially for application to the prediction of crystal structures. This is partly because the models for energy have not been accurate enough to warrant these, often time-consuming, calculations. Now that the methods for calculating the static energy have become reliable enough, at least for small molecules, the logical step is to use these accurate energy models to study motions within the crystals. This work will exploit recent developments in software, as well as developing programs that will be necessary for these calculations.
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