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Multiscale modelling to understand the self-assembly mechanism of human β2-adrenergic receptor in lipid bilayer

Paper ID Volume ID Publish Year Pages File Format Full-Text
15139 1381 2014 11 PDF Available
Title
Multiscale modelling to understand the self-assembly mechanism of human β2-adrenergic receptor in lipid bilayer
Abstract

•Self-assembly mechanism of β2-AR in membrane using multiscale modelling is reported.•β2-AR monomers are found to form oligomers after 10 μs CGMD simulation.•TM1, H8, TM5 and TM6 helices formed most of the dimerization surfaces.•Subtle helical rearrangements are required to form energetically favourable dimers.

The long perceived notion that G-Protein Coupled Receptors (GPCRs) function in monomeric form has recently been changed by the description of a number of GPCRs that are found in oligomeric states. The mechanism of GPCR oligomerization, and its effect on receptor function, is not well understood. In the present study, coarse grained molecular dynamics (CGMD) approach was adopted for studying the self-assembly process of the human GPCR, β2-adrenergic receptor (β2-AR), for which several experimental evidences of the dimerization process and its effect on cellular functions are available. Since the crystal structure of β2-AR lacks the third intracellular loop, initially it was modelled and simulated using restrained MD in order to get a stable starting conformation. This structure was then converted to CG representation and 16 copies of it, inserted into a hydrated lipid bilayer, were simulated for 10 μs using the MARTINI force field. At the end of 10 μs, oligomers of β2-AR were found to be formed through the self-assembly mechanism which were further validated through various analyses of the receptors. The lipid bilayer analysis also helped to quantify this assembly mechanism. In order to identify the domains which are responsible for this oligomerization, a reverse transformation of the CG system back to all-atom structure and simulated annealing run were carried out at the end of 10 μs CGMD run. Analysis of the all-atom dimers thus obtained, revealed that TM1/TM1, H8/H8, TM1/TM5 and TM6/TM6 regions formed most of the dimerization surfaces, which is in accordance with some of the experimental observations and recent simulation results.

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Keywords
GPCR; β2-AR; Oligomerization; CGMD; Simulated annealing; MARTINI
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Multiscale modelling to understand the self-assembly mechanism of human β2-adrenergic receptor in lipid bilayer
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 48, February 2014, Pages 29–39
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us