Small Molecules as Rotamers: Generation and Docking in ROSETTALIGAND

Abstract

We introduce small molecule rotamers into the rotamer search protocol used in Rosetta to model small molecule flexibility in docking. Rosetta, a premier protein modeling suite, models side chain flexibility using discrete conformations observed in the Protein Data Bank (PDB). We mimic this concept and build small molecule rotamers based on conformations from the Cambridge Structural Database. We eval- uate to the small molecule rotamer generation protocol on a test set of 628 conforma- tion,s taken from the PDBBind database, of small molecules with ≤ 6 rotable bonds. Our protocol generates ensembles in which the closest conformation is 0.45 ±0.31 ̊A RMSD from the crystallized conformation. Further, in a set of 21 small molecule pro- tein complexes, 16 of 21 cases a native-like model was in the top 1 % of models by energy.