Receptor ligand binding: complex structure prediction and affinity evaluation

• Applicants: Professor Dr. Rainer Böckmann; Professor Dr. Berend de Groot
• Subject Area: Biophysics
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 46076684

• Final Report Year: 2013

Final Report Abstract

Ligand-receptor binding plays an essential role throughout biology, forming the basis for processes as diverse as perception, transport, bioenergetics and enzyme catalysis. Likewise, the interaction of small compounds with biological receptors forms the basis for all forms of chemotherapy. Therefore, it is of crucial importance to understand the basis of ligand receptor interactions at the molecular level. One of the challenges in this respect if the dynamical nature of biomolecules. In this project, a severe limitation of established protocols, the assumption of a rigid receptor, has been overcome. Using simulated structure ensembles that explicitly account for flexibility, a vastly improved prediction of binding affinities has been demonstrated. Successful applications range from a quantitative prediction of the effect of protein and DNA mutation to the accurate prediction of the conformational changes ocurring upon ligand binding as well as the successful prediction of novel aquaporin-1 inhibitors, as recently confirmed experimentally.

Publications

• Predicting Free Energy Changes Using Structural Ensembles. Nature Methods. 6: 3-4 (2009)
  Alexander Benedix, Caroline M. Becker, Bert L. de Groot, Amedeo Caflisch, Rainer A. Böckmann
  
• tCONCOORD-GUI: Visually Supported Conformational Sampling of Bioactive Molecules. J. Comp. Chem. 30:1160-1166 (2009)
  Daniel Seeliger and Bert L. de Groot
  
• Thermodynamic signature of trapped water molecules in a protein-ligand interaction. Angewandte Chemie. 48:5207-5210 (2009)
  Christian M. Stegmann, Daniel Seeliger, George M. Sheldrick, Bert L. de Groot and Markus Wahl
  
• Conformational transitions upon ligand binding: Holo structure prediction from apo conformations. PLoS Comput. Biol. 6: e1000634 (2010)
  Daniel Seeliger and Bert L. de Groot
  
• Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J. Computer-aided Molec. Design. 24:417-422 (2010)
  Daniel Seeliger and Bert L. de Groot
  
• Protein thermostability calculations using alchemical free energy simulations. Biophys. J. 98:2309-2316 (2010)
  Daniel Seeliger and Bert L. de Groot
  
• Towards computional specificity screening of DNA-binding proteins. Nucleic Acids Research. 39: 8281-8290 (2011)
  Daniel Seeliger, Floris P. Buelens, Maik Goette, Bert L. de Groot and Helmut Grubmüller
  
• Dynamical characterization of two differentially disease-associated MHC Class I proteins in complex with viral and self-peptides. J. Mol. Biol. 415:429-442 (2012)
  Daniele Narzi, Caroline M. Becker, Maria Teresa Fiorillo, Barbara Uchanskao Ziegler, Andreas Ziegler, Rainer A. Böckmann
  (See online at https://doi.org/10.1016/j.jmb.2011.11.021)
• Discovery of Novel Human Aquaporin-1 Blockers. ACS Chem. Biol. 8:249-256 (2013)
  Daniel Seeliger, Cinta Zapater, Dawid Krenc, Rose Haddoub, Sabine Flitsch, Eric Beitz, Joan Cerda and Bert L. de Groot
  (See online at https://doi.org/10.1021/cb300153z)