Journal Article

FZJ-2018-06519

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study

Cao, R.FZJ* ; Giorgetti, A.FZJ* ; Bauer, A.FZJ* ; Neumaier, B.FZJ* ; Rossetti, G. (Corresponding author)FZJ* ; Carloni, P.FZJ*

2018
MDPI75390 Basel

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Please use a persistent id in citations: http://hdl.handle.net/2128/20118  doi:10.3390/molecules23102616

Abstract: Human G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2AR), a target for neuroprotective compounds. The ligand is the high-affinity antagonist (4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol), embedded in a neuronal membrane mimic environment. Free energy calculations, based on well-tempered metadynamics, reproduce the experimentally measured binding affinity. The results are consistent with the available mutagenesis studies. The calculations identify a vestibular binding site, where lipids molecules can actively participate to stabilize ligand binding. Bioinformatic analyses suggest that such vestibular binding site and, in particular, the second extracellular loop, might drive the ligand toward the orthosteric binding pocket, possibly by allosteric modulation. Taken together, these findings point to a fundamental role of the interaction between extracellular loops and membrane lipids for ligands’ molecular recognition and ligand design in hA2AR.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. Nuklearchemie (INM-5)
4. Molekulare Organisation des Gehirns (INM-2)
5. Jülich Supercomputing Center (JSC)

Research Program(s):

1. 571 - Connectivity and Activity (POF3-571) (POF3-571)
2. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)

Appears in the scientific report 2018

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Database coverage:
; ; ; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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