Free Energy-Based Conformational Search Algorithm Using the Movable Type Sampling Method

In this article, we extend the movable type (MT) sampling method to molecular conformational searches (MT-CS) on the free energy surface of the molecule in question. Differing from traditional systematic and stochastic searching algorithms, this method uses Boltzmann energy information to facilitate the selection of the best conformations. The generated ensembles provided good coverage of the available conformational space including available crystal structures. Furthermore, our approach directly provides the solvation free energies and the relative gas and aqueous phase free energies for all generated conformers. The method is validated by a thorough analysis of thrombin ligands as well as against structures extracted from both the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD). An in-depth comparison between OMEGA and MT-CS is presented to illustrate the differences between the two conformational searching strategies, i.e., energy-based versus free energy-based searching. These studies demonstrate that our MT-based ligand conformational search algorithm is a powerful approach to delineate the conformational ensembles of molecular species on free energy surfaces.