Pentameric ligand-gated ion channels (pLGIC) of the Cys-loop family mediate fastchemo-electrical transduction, which is modulated by general anesthetics and n-alcohols.For GLIC, a prokaryotic member of pLGIC, a single mutation turns Desfluranefrom an inhibitor to an activator. The location and properties of the exactinteraction sites of Desflurane are required to understand this mechanisms ofmodulation. Here, we have employed atomistic MD simulations and free energy perturbation tocalculate binding affinities for different conformations of Desflurane in the intra-and intermolecular binding sites of GLIC.For the WT the intramolecular binding site is favored by 5 kJ/mol, but through themutation the binding energy for Desflurane in the intermolecular site increases asmuch as 8 kJ/mol. Thus, we propose the differences in modulation of GLIC by Desflurane is a resultof the difference in binding affinities between intra- and intermolecular sites.

Single-site mutation changes the location of the most favored Desflurane binding site in the GLIC ligand-gated ion channel

243rd National Meeting (2012)

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