Energy-directed tree search: an efficient systematic algorithm for finding the lowest energy conformation of molecules

Abstract

We present a new systematic algorithm, energy-directed tree search (EDTS), for exploring the conformational space of molecules. The algorithm has been designed to reliably locate the global minimum (or, in the worst case, a structure within 4 kJ mol⁻¹ of this species) at a fraction of the cost of a full conformational search, and in this way extend the range of chemical systems for which accurate thermochemistry can be studied. The algorithm is inspired by the build-up approach but is performed on the original molecule as a whole, and objectively determines the combinations of torsional angles to optimise using a learning process. The algorithm was tested for a set of 22 large molecules, including open- and closed-shell species, stable structures and transition structures, and neutral and charged species, incorporating a range of functional groups (such as phenyl rings, esters, thioesters and phosphines), and covering polymers, peptides, drugs, and natural products. For most of the species studied the global minimum energy structure was obtained; for the rest the EDTS algorithm found conformations whose total electronic energies are within chemical accuracy from the true global minima. When the conformational space is searched at a resolution of 120°, the cost of the EDTS algorithm (in its worst-case scenario) scales as 2^N for large N (where N is the number of rotatable bonds), compared with 3^N for the corresponding systematic search.