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.