Energy minimization of crystal structures containing flexible molecules

This paper proposes a new methodology for the accurate minimization of crystal structures of flexible molecules. The intramolecular contributions to the crystal energy are calculated from ab initio calculations and appear well-balanced with the intermolecular interactions being evaluated via a conformation-dependent distributed multipole model in conjunction with an empirical repulsion-dispersion potential model. The validity of the methodology was initially tested by minimizing the experimental crystal structures of a set of flexible molecules. In a more stringent test, the methodology was used to refine the low-energy structures found in rigid-body crystal structure prediction studies of the diastereomeric salt pair (R)-1-phenylethylammonium (R/S)-2-phenylpropanoate and the antiepileptic drug carbamazepine. The refinement improved the relative stability of the known forms and their ranking in the list of hypothetically generated structures by leading to energetically more favorable hydrogen-bond geometries and dispersion interactions.