Large-scale QM/MM calculations of protein-ligand interaction in Thrombin S1 pocket

COMP 206

Marek Freindorf, marek@q-chem.com1, Jing Kong1, Bernhard Baum, bernhard.baum@staff.uni-marburg.de2, Menshawy Mohamed, mm323@buffalo.edu3, Mohamed Zayed, mfzayed@buffalo.edu3, Gerhard Klebe, klebe@staff.uni-marburg.de2, and David G. Hangauer, hangauer@buffalo.edu3. (1) Q-Chem, Inc, 5001 Baum Blvd., Suite 690, Pittsburgh, PA 15213, (2) Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, Marburg, 35032, Germany, (3) Department of Chemistry, University at Buffalo, The State University of New York, Natural Sciences Complex, Box 603000, Buffalo, NY 14260-3000
Thrombin is a human protein converting fibrinogen into fibrin, which can lead to stocks and heart attacks. It has been discovered that a meta-chloro benzyl side chain of a protein inhibitor (ligand), is responsible for high binding affinity in the thrombin S1 pocket. We have calculated the interaction energy between the ligand and the protein for a series of the most reported potent thrombin inhibitors, which consisted of a meta halogen (X), as well as a second halogen at the ortho position (Y). The calculations have been performed using a large-scale quantum-mechanical molecular-mechanical (QM/MM) approach, which is based on a long molecular dynamics (MD) followed by a series of individual QM/MM calculations, randomly selected from a MD trajectory [submitted to JACS]. The MD simulations have been performed for the protein with the ligand in a TIP3P water sphere of a radius 50A, for 10ns at constant temperature and volume using AMBER program. The similar MD has been performed for the ligand alone in TIP3P water solution for 5ns. After MD, 600 protein structures have been randomly selected and for each protein snapshot, geometry of the ligand has been QM optimized in the fixed MM protein matrix using Q-Chem program. The similar QM/MM calculations have been performed for the ligand alone in water solution. The interaction energy was calculated as an energy difference between an average energy of the ligand in the protein and an average energy of the ligand in water. The overall correlation was observed in our study between the calculated interaction energy and the measured ITC enthalpy of binding for the selected thrombin inhibitors. The unusual binding affinity of the meta-chloro ligand is explained in our study by its small desolvation energy.
 

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Division of Computers in Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009