Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Generating Conformational Ensembles for Flexible Protein-Ligand Docking by Elastic Network Model Guided Molecular Dynamics Simulations: Application to Beta 2 Adrenergic Receptor

Studying the entire motion spectrum of a protein is necessary for a complete understanding of its function(s). However, this is not trivial since protein motions are complex ranging from femtosecond scale local atomic vibrations to millisecond scale large motions. We previously developed Anisotropic Network Model (ANM) restrained Molecular dynamics (MD) that takes advantage of these two complementing methods to sample long time scale biologically relevant global motions of a biomolecular system with realistic deformations favored by a detailed atomic force field in the presence of the explicit environment (1). Here, we use ANM-restrained-MD method to generate conformational ensembles of a pharmacologically relevant G-protein Coupled Receptor (GCPR), Beta 2 Adrenergic Receptor (β2AR). It has been shown that the binding of GPCRs to structurally diverse ligands and their activation is a complex process that requires these receptors passing through multiple conformationally distinct states (2,3). Along with the existing crystal structures, the conformational ensembles are utilized for understanding the dynamics and binding modes of β2AR to its known agonists by performing docking against them. We observe that the residues Ser203, Ser204, and Ser207 on H5 become accessible at the ligand binding site by the rotation of H5. Additional to Serines on H5, Val114 and Thr118 on H3 and “the rotamer toggle switch”, Phe290, on H6 stabilize the aromatic rings and the catecholamine moieties of the agonists of β2AR by forming hydrogen bonds and phi-stacking interactions. Furthermore, our study also shows that the long acting agonist drug that is currently prescribed for asthma, salmeterol, folds uniquely at the ligand binding pocket of β2AR and stabilizes its extracellular region of forming a “beta sheet-like” structure with the extracellular loop 2.

Authors would like to thank Drs Ivet Bahar, Klaus Schulten and Emad Tajhkorshid for their valuable contributions during the development of ANM-guided-MD algorithm.


  1. B. Isin, K. Schulten, E. Tajkhorshid, and I. Bahar, Biophys. J. 95, 789-803 (2008).
  2. G. Liapakis, W.C. Chan, M. Papadokosktaki, and J.M. Javitch, Mol. Pharmacol. 65, 1181-1190 (2004).
  3. B.K. Kobilka, and X. Deupi, Trends Pharmacol. Sci. 28, 397-406 (2007).

Basak Isin1
Guillermina Estiu2
Olaf Wiest2
Zoltan N. Oltvai1

1Department of Pathology
Computational & Systems Biology
University of Pittsburgh
Pittsburgh, PA, 15261 USA
2Department of Chemistry and Biochemistry
University of Notre Dame
Notre Dame, IN, 46556 USA

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