Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I

5-POS Board 5 Investigating the Allosteric Mechanism in Human β2-adrenergic Receptor (β2AR) upon Activation/Inactivation via Constrained Molecular Dynamics (MD) Simulation Canan Özgür 1 , Pemra Doruker 2 , Ebru D. Akten 3 . 3 Kadir Has University, Istanbul, Turkey. 2 Bogazici University, Istanbul, Turkey, 1 Bogazici University, Istanbul, Turkey As the member of G-protein coupled receptor (GPCR) superfamily β2AR is involved in a wide range of physiological processes such as the regulation of heart rate and muscle relaxation in lung tissues. In this study, the allosteric coupling that involves the intra- and extracellular parts of the receptor will be investigated via MD simulations under various distance constraints. Several crystallographic structures of both active and inactive states of β2AR were revealed, yet none included the intracellular loop 3 (ICL3), which was cleaved prior to experiments to facilitate crystallization. This critical region of 32-residues was generated through homology modeling and incorporated in the receptor model due to its potential effect on the intrinsic dynamics of β2AR as previously reported in our MD study. Several MD runs under various distance constraints applied to selected residues were performed using NAMD in order to reveal the allosteric coupling. The receptor was embedded in a POPC membrane bilayer with explicit water, to generate a system of 68,000 atoms. Allosteric coupling between intra- and extracellular parts of the receptor was revealed during 500 ns long MD runs under various constraints. Previously, a 1 μs long MD simulation conducted without any constraints showed that the closure of the G protein binding site as a result of a tightly packed ICL3 under the receptor was paired with the expansion of the ligand binding site as indicated by the increase in Ser207-Asp113 distance. In constrained MD runs, same coupling was once more confirmed. As the binding site is kept open, ICL3 is guided to a closed position, and vice versa. Furthermore, the closure of ICL3 under the receptor provided a new inactive state, which becomes a potential target for drug design studies.

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