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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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The GABA binding sites consisting of residues Phe146, Glu204, Phe206, Tyr254, Tyr109, Arg111 and Ser176, in the optimized homology models before GABA docking: a RDL-AChBP; b RDL-ELIC; c RDL-GluCl1; d RDL-GluCl2. The displacement of each atom from its position in the RDL-GluCl2 model is highlighted
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Fig3: The GABA binding sites consisting of residues Phe146, Glu204, Phe206, Tyr254, Tyr109, Arg111 and Ser176, in the optimized homology models before GABA docking: a RDL-AChBP; b RDL-ELIC; c RDL-GluCl1; d RDL-GluCl2. The displacement of each atom from its position in the RDL-GluCl2 model is highlighted

Mentions: Electrophysiology mutagenesis experiments have identified residues Arg111, Glu204, Tyr109, Tyr254 and Phe206 as important for neurotransmitter binding; Ser176 and Phe146 may also play a role [17, 18]. These seven amino acids (Phe146, Glu204, Phe206 and Tyr254 in the principal subunit and Tyr109, Arg111 and Ser176 in the complementary subunit) are highlighted in the models of Fig. 2, showing the location of one of the five equivalent binding sites in the pentameric structure and, on a larger scale, in Fig. 3, where the relative differences can be observed.Fig. 3


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)

The GABA binding sites consisting of residues Phe146, Glu204, Phe206, Tyr254, Tyr109, Arg111 and Ser176, in the optimized homology models before GABA docking: a RDL-AChBP; b RDL-ELIC; c RDL-GluCl1; d RDL-GluCl2. The displacement of each atom from its position in the RDL-GluCl2 model is highlighted
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: The GABA binding sites consisting of residues Phe146, Glu204, Phe206, Tyr254, Tyr109, Arg111 and Ser176, in the optimized homology models before GABA docking: a RDL-AChBP; b RDL-ELIC; c RDL-GluCl1; d RDL-GluCl2. The displacement of each atom from its position in the RDL-GluCl2 model is highlighted
Mentions: Electrophysiology mutagenesis experiments have identified residues Arg111, Glu204, Tyr109, Tyr254 and Phe206 as important for neurotransmitter binding; Ser176 and Phe146 may also play a role [17, 18]. These seven amino acids (Phe146, Glu204, Phe206 and Tyr254 in the principal subunit and Tyr109, Arg111 and Ser176 in the complementary subunit) are highlighted in the models of Fig. 2, showing the location of one of the five equivalent binding sites in the pentameric structure and, on a larger scale, in Fig. 3, where the relative differences can be observed.Fig. 3

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