Ensemble Docking Interrogates Structural Determinants of Ligand-Protein Interactions

Vanderbilt University, Nashville TN

Investigators

Abstract

With this award, the Chemistry of Life Processes Program in the Chemistry Division at NSF is supporting the work of Dr. Jens Meiler of Vanderbilt university on an international collaborative effort to develop a new and potentially generally useful ensemble docking method for the RosettaLigand molecular modeling program. The German team inthis collaboration will be led by Drs. Annette Beck-Sickinger and Torsten Schoenefeld at U. Leipzig and will be supported by the DFG (Deutsche Forschungsgemeinschaft), and represents the experimental side of the collaboration. The ensemble docking approach to be taken involves simultaneous docking of multiple ligands while considering experimental SAR (Structure-Activity Relationships) as part of the scoring function. The collaborative team has selected the family of G-protein-coupled 7-(helix) transmembrane receptors (GPCRs) and ligand candidates as a platform upon which to develop this methodology. The German partnering team will take a natural product-inspired approach to ligand development/binding assessment for these receptors. Given the importance of protein-membrane receptor interactions across chemical biology, the proposed research aims at developing in silico methodology with potentially broad applicability to the community. Indeed success here and the possibility for disseminating the envisioned RosettaEnsembleDock module to the community would constitute arguably the most important scientific broader impact of this collaborative effort. The importance of GPCRs in signal transduction in biology cannot be overstated and therefore the model system upon which this computational algorithm is being built is also of considerable significance. The project will provide for interdisciplinary and international student training and exchange, and for the synergistic interaction of experimental protein-ligand binding team in Germany with a computational modeling/algorithm development team in the United States.