A Mining-Minima Approach to Exploring the Docking Pathways of p-Nitrocatechol Sulfate to YopH

¹ University of Missouri-Saint Louis

^* To whom correspondence should be addressed. E-mail: wongch{at}umsl.edu.

Submitted on May 29, 2007
Revised on July 26, 2007
Accepted on 2 August 2007

	Abstract

Using the docking of p-nitrocatechol sulfate (pNCS) to Yersinia protein tyrosine phosphatase YopH as an example, we showed that an approach based on mining minima followed by cluster and similarity analysis could generate useful insights into docking pathways. Our simulation treated both the ligand and the protein as flexible molecules so that the coupling between their motion could be properly accounted for. Our simulation identified three docking poses, the one with the lowest energy agreed well with experimental structure. The model also predicted the side-chain conformations of the amino acids lying in the binding pocket correctly with the exception of three residues that appeared to be stabilized by two structural water molecules in the crystal structure. The implicit-solvent model employed in the simulation could not capture such effects well. We also found four major pathways leading to these docking poses after the ligand entered the mouth of the binding pocket. In addition, the sulfate group of pNCS was found to be important both in binding the ligand to the pocket and in guiding the ligand to dock into the pocket. The coupling of the motion between the protein and the ligand also played an important role in facilitating ligand loading and unloading.

Key Words: clustering, flexible-ligand flexible-protein docking, molecular dynamics, similarity analysis, simulated annealing