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Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models.

Comitani F, Cohen N, Ashby J, Botten D, Lummis SC, Molteni C - J. Comput. Aided Mol. Des. (2014)

Bottom Line: The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template.Overall, we show that the GluCl template provided the best models.GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.

View Article: PubMed Central - PubMed

Affiliation: Physics Department, King's College London, Strand, London, WC2R 2LS, UK.

ABSTRACT
The resistance to dieldrin (RDL) receptor is an insect pentameric ligand-gated ion channel (pLGIC). It is activated by the neurotransmitter γ-aminobutyric acid (GABA) binding to its extracellular domain; hence elucidating the atomistic details of this interaction is important for understanding how the RDL receptor functions. As no high resolution structures are currently available, we built homology models of the extracellular domain of the RDL receptor using different templates, including the widely used acetylcholine binding protein and two pLGICs, the Erwinia Chrysanthemi ligand-gated ion channel (ELIC) and the more recently resolved GluCl. We then docked GABA into the selected three dimensional structures, which we used as starting points for classical molecular dynamics simulations. This allowed us to analyze in detail the behavior of GABA in the binding sites, including the hydrogen bond and cation-π interaction networks it formed, the conformers it visited and the possible role of water molecules in mediating the interactions; we also estimated the binding free energies. The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template. We supplemented the molecular dynamics information with metadynamics, a rare event method, by exploring the free energy landscape of GABA binding to the RDL receptor. Overall, we show that the GluCl template provided the best models. GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.

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Left: Free energy map of GABA in the RDL-GluCl1 model as a function of the distance of the GABA amine from Glu204 side chain (CVGlu) and of the GABA carboxylate from the Arg111 side chain (CVArg). Right: Binding arrangements corresponding to the free energy minima
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Fig8: Left: Free energy map of GABA in the RDL-GluCl1 model as a function of the distance of the GABA amine from Glu204 side chain (CVGlu) and of the GABA carboxylate from the Arg111 side chain (CVArg). Right: Binding arrangements corresponding to the free energy minima

Mentions: The free energy landscape of GABA binding to the RDL receptor was explored by metadynamics as a function of the distance of the negatively charged carboxylate group of GABA from the side chain of Arg111 and that of the positively charged GABA amine from the side chain of Glu204, as detailed in the Methods section. Results for RDL-GluCl1 are reported in Fig. 8 as an example, showing an elongated basin of attraction corresponding to a range of relative distances between the amine and Glu204, while the GABA carboxylate was clearly pinned to Arg111. Two minima separated by a small barrier can be identified, related to the binding configurations shown on the right of Fig. 8: in one case (bottom) the amine group of GABA, which is in its extended conformer, is closer to Glu204 and forms a direct hydrogen bond; in the other case (top) GABA is in a bent conformation and forms a water mediated hydrogen bond.Fig. 8


Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models.

Comitani F, Cohen N, Ashby J, Botten D, Lummis SC, Molteni C - J. Comput. Aided Mol. Des. (2014)

Left: Free energy map of GABA in the RDL-GluCl1 model as a function of the distance of the GABA amine from Glu204 side chain (CVGlu) and of the GABA carboxylate from the Arg111 side chain (CVArg). Right: Binding arrangements corresponding to the free energy minima
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3927061&req=5

Fig8: Left: Free energy map of GABA in the RDL-GluCl1 model as a function of the distance of the GABA amine from Glu204 side chain (CVGlu) and of the GABA carboxylate from the Arg111 side chain (CVArg). Right: Binding arrangements corresponding to the free energy minima
Mentions: The free energy landscape of GABA binding to the RDL receptor was explored by metadynamics as a function of the distance of the negatively charged carboxylate group of GABA from the side chain of Arg111 and that of the positively charged GABA amine from the side chain of Glu204, as detailed in the Methods section. Results for RDL-GluCl1 are reported in Fig. 8 as an example, showing an elongated basin of attraction corresponding to a range of relative distances between the amine and Glu204, while the GABA carboxylate was clearly pinned to Arg111. Two minima separated by a small barrier can be identified, related to the binding configurations shown on the right of Fig. 8: in one case (bottom) the amine group of GABA, which is in its extended conformer, is closer to Glu204 and forms a direct hydrogen bond; in the other case (top) GABA is in a bent conformation and forms a water mediated hydrogen bond.Fig. 8

Bottom Line: The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template.Overall, we show that the GluCl template provided the best models.GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.

View Article: PubMed Central - PubMed

Affiliation: Physics Department, King's College London, Strand, London, WC2R 2LS, UK.

ABSTRACT
The resistance to dieldrin (RDL) receptor is an insect pentameric ligand-gated ion channel (pLGIC). It is activated by the neurotransmitter γ-aminobutyric acid (GABA) binding to its extracellular domain; hence elucidating the atomistic details of this interaction is important for understanding how the RDL receptor functions. As no high resolution structures are currently available, we built homology models of the extracellular domain of the RDL receptor using different templates, including the widely used acetylcholine binding protein and two pLGICs, the Erwinia Chrysanthemi ligand-gated ion channel (ELIC) and the more recently resolved GluCl. We then docked GABA into the selected three dimensional structures, which we used as starting points for classical molecular dynamics simulations. This allowed us to analyze in detail the behavior of GABA in the binding sites, including the hydrogen bond and cation-π interaction networks it formed, the conformers it visited and the possible role of water molecules in mediating the interactions; we also estimated the binding free energies. The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template. We supplemented the molecular dynamics information with metadynamics, a rare event method, by exploring the free energy landscape of GABA binding to the RDL receptor. Overall, we show that the GluCl template provided the best models. GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.

Show MeSH
Related in: MedlinePlus