Exploring Conformational Dynamics of the Extracellular Venus flytrap Domain of the GABA B Receptor: A Path-Metadynamics Study
| Autor: | Ingebrigt Sylte, Riccardo Ocello, Linn Samira Mari Evenseth, Matteo Masetti, Maurizio Recanatini, Andrea Cavalli, Mari Gabrielsen |
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| Přispěvatelé: | Evenseth, Linn S M, Ocello, Riccardo, Gabrielsen, Mari, Masetti, Matteo, Recanatini, Maurizio, Sylte, Ingebrigt, Cavalli, Andrea |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
010304 chemical physics
Chemistry Drug discovery General Chemical Engineering Metadynamics Drug design VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 General Chemistry Library and Information Sciences GABAB receptor 01 natural sciences gamma-Aminobutyric acid VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry 0103 physical sciences medicine Biophysics free energy path metadynamics conformational transition Binding site Receptor medicine.drug G protein-coupled receptor |
| Popis: | γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). Dysfunctional GABAergic neurotransmission is associated with numerous neurological and neuropsychiatric disorders. The GABAB receptor (GABAB-R) is a heterodimeric class C G protein-coupled receptor (GPCR) comprised of GABAB1a/b and GABAB2 subunits. The orthosteric binding site for GABA is located in the extracellular Venus flytrap (VFT) domain of the GABAB1a/b. Knowledge about molecular mechanisms and druggable receptor conformations associated with activation is highly important to understand the receptor function and for rational drug design. Currently, the conformational changes of the receptor upon activation are not well described. On the basis of other class C members, the VFT is proposed to fluctuate between an open/inactive and closed/active state and one of these conformations is stabilized upon ligand binding. In the present study, we investigated the dynamics of the GABAB1b-R VFT in the apo form by combining unbiased molecular dynamics with path-metadynamics. Our simulations confirmed the open/inactive and closed/active state as the main conformations adopted by the receptor. Sizeable energy barriers were found between stable minima, suggesting a relatively slow interconversion. Previously undisclosed metastable states were also identified, which might hold potential for future drug discovery efforts. |
| Databáze: | OpenAIRE |
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