Étude de l'anesthésie générale à l'échelle atomique par modélisation d'un homologue bactérien du récepteur nicotinique humain

Abstract : The discovery of anesthetic molecules represents a notable advance in medecine, mostly enabled by empirically observing their effect. In vitro experiments uncovered neuroreceptors as possible target for anesthetic molecules. Those are membrane-bound ion channels located on the target cells at nervous endings. In the last few years, bacterial neuroreceptor homologs were identified. The GLIC receptor, a homopentamer homologue to the human nicotinic receptor, was co-crystallized with bound general anesthetics, including bromoform, desflurane and propofol. In this thesis, I use molecular dynamics simulations and software programming to characterize interactions of general anesthetics with the wild type form of GLIC as well as with several mutants. In 2011, propofol and desflurane were co-crystallized in an intrasubunit binding site located in GLIC's transmembrane domain. More recently, bromoform was shown to bind this site as well as an intersubunit site. In this work I describe simulations of a new crystal structure displaying an additional binding site located in the channel's pore. Simulations in which GLIC is flooded by bromoform demonstrate the spontaneous accessibility of crystallographic binding sites in a non-crystalline environment. Exhaustive free energy calculations corroborate this data highlighting differences of binding energy between sites and between GLIC variants. Extensive sampling of binding pockets allowed me to detect a second intersubunit binding site, the accessibility of which is possibly modulated by a specific residue. Alltogether, data accumulated in this project provide a growing picture of anesthetic action at the atomic scale.
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Submitted on : Wednesday, July 30, 2014 - 10:56:43 PM
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Benoist Laurent. Étude de l'anesthésie générale à l'échelle atomique par modélisation d'un homologue bactérien du récepteur nicotinique humain. Biochimie [q-bio.BM]. Université Paris-Diderot - Paris VII, 2014. Français. ⟨tel-01053431⟩

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