Journal Article

FZJ-2020-00486

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Modeling the allosteric modulation on a G-Protein Coupled Receptor: the case of M2 muscarinic Acetylcholine Receptor in complex with LY211960

Maggi, L. (Corresponding author)FZJ* ; Carloni, P.FZJ* ; Rossetti, G.FZJ*

2020
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: http://hdl.handle.net/2128/24401  doi:10.1038/s41598-020-59289-5

Abstract: Allosteric modulation is involved in a plethora of diverse protein functions, which are fundamental for cells’ life. This phenomenon can be thought as communication between two topographically distinct site of a protein structure. How this communication occurs is still matter of debate. Many different descriptions have been presented so far. Here we consider a specific case where any significant conformational change is involved upon allosteric modulator binding and the phenomenon is depicted as a vibrational energy diffusion process between distant protein regions. We applied this model, by employing computational tools, to the human muscarinic receptor M2, a transmembrane protein G-protein coupled receptor known to undergo allosteric modulation whose recently X-ray structure has been recently resolved both with and without the presence of a particular allosteric modulator. Our calculations, performed on these two receptor structures, suggest that for this case the allosteric modulator modifies the energy current between functionally relevant regions of the protein; this allows to identify the main residues responsible for this modulation. These results contribute to shed light on the molecular basis of allosteric modulation and may help design new allosteric ligands.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. Jülich Supercomputing Center (JSC)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)
2. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)

Appears in the scientific report 2020

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