Small Molecule Rotamers Enable Simultaneous Optimization of Small Molecule and Protein Degrees of Freedom in ROSETTALIGAND Docking

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 evaluate the small molecule rotamer generation protocol on a test set of 628 conformations, taken from the PDBBind database, of small molecules with ≤ 6 rotatable bonds. Our protocol generates ensembles in which the closest conformation on average is 0.45 ± 0.31 Å RMSD from the crystallized conformation. Furthermore, in two sets of docking benchmarks the native ligand position and conformation is found within the top 1 % of models by energy in 72% and 90% of all cases.

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