Transmembrane helix 6 observed at the interface of β<sub>2</sub>AR homodimers in blind docking studies

2015-04-28T11:33:56Z (GMT) by Ayca Koroglu Ebru Demet Akten
<div><p>Peptide– and protein–protein dockings were carried out on β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two β<sub>2</sub>AR monomers, thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially, a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to β<sub>2</sub>AR monomer using a rigid body approach. Interestingly, all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore, longer peptides generated from a whole TM region were blindly docked to β<sub>2</sub>AR using the same rigid body approach. This yielded a total of seven docked peptides, each derived from one TM helix. Most interestingly, for each peptide, TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings, two β<sub>2</sub>AR monomers were blindly docked to each other using a full rigid-body search of docking orientations, which yielded a total of 16,000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements, 102 conformers were composed of two monomers oriented in opposite directions, whereas in the remaining 47, the monomers were arranged in parallel. Lastly, all 149 conformers were clustered based on a root mean-squared distance value of 6 Å. In agreement with the peptide results, the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.</p></div>