Ab Initio Crystal Structure Prediction for Flexible Molecules

A three-stage lattice energy minimisation methodology is reported for the identification of stable crystal structures containing flexible molecules. The accuracy of the approach is improved from stage to stage by using increasingly accurate models, first by substituting an atomic charge model with a distributed multipole model computed from the isolated-molecule charge density, and then by allowing user-defined molecular flexibility. When using the most sophisticated model, the computational cost is kept manageable by the use of local approximate models (LAMs) to estimate the conformationally dependent intramolecular energy and charge density and the reuse of quantum mechanical calculations stored in a molecule-specific databases. The applicability of the approach is illustrated by the generation of crystal structures with one molecule in the asymmetric unit for hydroquinone. The methodology combines an extensive search with accurate models for the lattice energy and can be equally applied to single and multi-component systems, such as cocrystals, salts and hydrates.