Automated site preparation in physics-based rescoring of receptor ligand complexes

Hydrogen atoms are not typically observable in X-ray crystal structures, but inferring their locations is often important in structure-based drug design. In addition, protonation states of the protein can change in response to ligand binding, as can the orientations of OH groups, a subtle form of "induced fit." We implement and evaluate an automated procedure for optimizing polar hydrogens in protein-binding sites in complex with ligands. Specifically, we apply the previously described Independent Cluster Decomposition Algorithm (ICDA) algorithm (Li et al., Proteins 2007;66:824-837), which assigns the ionization states of titratable residues, the amide orientations of Asn/Gln side chains, the imidazole ring orientation in His, and the orientations of OH/SH groups, in a unified algorithm. We test the utility of this method for identifying nativelike ligand poses using 247 protein-ligand complexes from an established database of docked decoys. Pose selection is performed with a physics-based scoring function based on a molecular mechanics energy function and a Generalized Born implicit solvent model. The use of the ICDA receptor preparation protocol, implemented with no knowledge of the native ligand pose, increases the accuracy of pose selection significantly, with the average RMSD over all complexes decreasing from 2.7 to 1.5 A when applying ICDA. Large improvements are seen for specific classes of binding sites with titratable groups, such as aspartyl proteases.