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  • 1.
    Murail, Samuel
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Wallner, Björn
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Trudell, James R.
    Bertaccini, Edward
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Microsecond Simulations Indicate that Ethanol Binds between Subunits and Could Stabilize an Open-State Model of a Glycine Receptor2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 7, p. 1642-1650Article in journal (Refereed)
    Abstract [en]

    Cys-loop receptors constitute a superfamily of ion channels gated by ligands such as acetylcholine, serotonin, glycine, and gamma-aminobutyric acid. All of these receptors are thought to share structural characteristics, but due to high sequence variation and limited structure availability, our knowledge about allosteric binding sites is still limited. These sites are frequent targets of anesthetic and alcohol molecules, and are of high pharmacological importance. We used molecular simulations to study ethanol binding and equilibrium exchange for the homomeric alpha 1 glycine receptor (GlyR alpha 1), modeled on the structure of the Gloeobacter violaceus pentameric ligand-gated channel. Ethanol has a well-known potentiating effect and can be used in high concentrations. By performing two microsecond-scale simulations of GlyR with/without ethanol, we were able to observe spontaneous binding in cavities and equilibrium ligand exchange. Of interest, it appears that there are ethanol-binding sites both between and within the GlyR transmembrane subunits, with the intersubunit site having the highest occupancy and slowest exchange (similar to 200 ns). This model site involves several residues that were previously identified via mutations as being crucial for potentiation. Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors.

  • 2.
    Schwaiger, Christine S.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Cell Biology, Linköping, Sweden.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Wallner, Björn
    The voltage sensor deactivation barrier is altered by substitutions in the hydrophobic coreManuscript (preprint) (Other academic)
    Abstract [en]

    The gating of voltage-gated ion channels is caused by the arginine-rich S4 helix of the voltage sensor moving in response to an external potential. Exactly how this is accomplished is not yet fully known, but several studies now indicate S4 transiently adopts 310-conformation to facilitate the process. Here, we combine modeling of intermediate states based on experimental constraints with systematic in silico mutagenesis and free energy calculations to identify metastable states and characterize the energetics when moving between them. We show that states very close to the X-ray structure can be obtained with steered simulations starting from the intermediate state, and that several residues in the narrow hydrophobic band in the middle of the voltage sensor contribute to the free energy between the activated and intermediate states. The single most important is the structural barrier caused by the aromatic ring of F233. Substitution for smaller amino acids reduces the translation cost signi cantly, while introduction of a larger ring increases it, both con rming experimental activation shift results. In fact, the rigid ring appears to determine the barrier for the voltage sensor gating process, with a close interaction between the ring rotation and the arginine barrier crossing.

     

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