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@PHDTHESIS{Kostritskii:854710,
      author       = {Kostritskii, Andrei},
      othercontributors = {Machtens, Jan-Philipp and Carloni, Paolo and Fitter, Jörg},
      title        = {{A}tomic-level insights into ion conduction and ion
                      selectivity of {TMEM}16 lipid scramblases},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2022-09731},
      pages        = {1 Online-Ressource : Illustrationen, Diagramme},
      year         = {2022},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, RWTH Aachen University, 2022},
      abstract     = {Lipid scramblases of the TMEM16 family are Ca$^{2+}$
                      -activated membrane proteins that provide a pathway for
                      bidirectional transport of lipids between the membrane
                      leaflets. Many TMEM16 lipid scramblases also function as ion
                      channels with implications in various physiological
                      processes, including apoptosis, immune response, and cell
                      volume regulation. Although physiological functions of ion
                      channels heavily rely on their ion selectivity, that of
                      TMEM16 lipid scramblases remains elusive, demonstrating a
                      notable variation among the experimental studies. Despite
                      recent progress in structural characterization of TMEM16
                      lipid scramblases, the molecular mechanisms of their ion
                      conduction and ion selectivity remain poorly understood.
                      Here, we used atomistic molecular dynamics (MD) simulations,
                      as a means for bridging static structural and macroscopic
                      functional data, to unravel atomic-level details of ion
                      channel functionality of TMEM16 lipid scramblases. We
                      utilized the recently developed computational
                      electrophysiology algorithm, which mimics functionality of
                      patch-clamp experimental setup, to study ion conduction
                      properties of fungal nhTMEM16 and human TMEM16K in various
                      lipid membranes. We found that in the main ion conductive
                      state TMEM16 lipid scramblases conduct ions through a
                      structured but yet dynamic proteolipidic pore, which is
                      partly formed by lipid headgroups. Lining the ion permeation
                      pathway, lipid headgroups directly interact with permeating
                      ions and shape the energetics of the ion permeation process.
                      Notably, due to the dipole moment associated with lipid
                      headgroups, their effect on the ion energetics depends on
                      polarity of the applied voltage, making the headgroups a
                      voltage-sensitive element of the pore. Moreover, our
                      simulations demonstrated that lipid headgroups which flank
                      the neck region of the pore can directly affect its
                      permeability. We also found that positioning and orientation
                      of charged residues in the pore of a TMEM16 lipid scramblase
                      define its basic ion selectivity, which, however, can be
                      prominently altered by membrane lipid composition via
                      changing the pore electrostatics. We identified the regions
                      with changed electrostatic potential by applying a new tool
                      $g\_elpot$, which we developed for quantifying biomolecular
                      electrostatics from MD trajectories. Concluding, in this
                      work we defined the structural basis of ion conduction and
                      selectivity in TMEM16 lipid scramblases and discovered the
                      direct effects of membrane lipids on the ion-conduction
                      properties of these dual function proteins.},
      cin          = {528500-3 / 137810 / 130000},
      ddc          = {530},
      cid          = {$I:(DE-82)528500-3_20140620$ / $I:(DE-82)137810_20140620$ /
                      $I:(DE-82)130000_20140620$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2022-09731},
      url          = {https://publications.rwth-aachen.de/record/854710},
}