Research Article: Towards Ligand Docking Including Explicit Interface Water Molecules

Date Published: June 28, 2013

Publisher: Public Library of Science

Author(s): Gordon Lemmon, Jens Meiler, Yaakov Koby Levy.


Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta’s ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9∶1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

Partial Text

Small molecule docking methods predict the structure of a protein/ligand complex [2]. Ligand docking consists of two components: sampling of the conformational space, and scoring of the resultant structures [3]. Sampling of the conformational space typically includes ligand position with respect to the protein often called ‘pose’), ligand conformation, and protein conformation. Scoring seeks to distinguish correct from incorrect binding poses by estimating binding affinity. It is characterized by a trade-off between accuracy and speed [3], [4]. While current sampling and scoring algorithms are often able to predict the correct binding pose [5], satisfactory prediction of binding affinity has yet to be achieved [4]. One particular challenge in ligand docking studies is the positioning of interface water molecules [5].