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Water and Hydrophobic Gates in Ion Channels and Nanopores

Abstract

Ion channel proteins form nanopores in biological membranes which allow the passage of ions and water molecules. Hydrophobic constrictions in such pores can form gates, i.e. energetic barriers to water and ion permeation. Molecular dynamics simulations of water in ion channels may be used to assess whether a hydrophobic gate is closed (i.e. impermeable to ions) or open. If there is an energetic barrier to water permeation then it is likely that a gate will also be impermeable to ions. Simulations of water behaviour have been used to probe hydrophobic gates in two recent ion channel structures: BEST1 and TMEM175. In each of these channels a narrow region is formed by three consecutive rings of hydrophobic sidechains and in both cases such analysis demonstrates that the crystal structures correspond to a closed state of the channel. In silico mutations of BEST1 have also been used to explore the effect of changes in the hydrophobicity of the gating constriction, demonstrating that substitution of hydrophobic sidechains by more polar sidechains results in an open gate which allows water permeation. A possible open state of the TMEM175 channel was modelled by in silico expansion of the hydrophobic gate resulting in wetting of the pore and free permeation of potassium ions through the channel. Finally, a preliminary study suggests that a hydrophobic gate motif can be transplanted in silico from the BEST1 channel into a simple β-barrel pore template. Overall, these results suggest that simulations of the behaviour of water in hydrophobic gates can reveal important design principles for the engineering of gates in novel biomimetic nanopores.

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Publication details

The article was accepted on 13 Feb 2018 and first published on 16 Apr 2018


Article type: Paper
DOI: 10.1039/C8FD00013A
Citation: Faraday Discuss., 2018, Accepted Manuscript
  • Open access: Creative Commons BY license
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    Water and Hydrophobic Gates in Ion Channels and Nanopores

    S. Rao, C. Lynch, G. Klesse, G. E. Oakley, P. Stansfeld, S. Tucker and M. Sansom, Faraday Discuss., 2018, Accepted Manuscript , DOI: 10.1039/C8FD00013A

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