title: Hydrophobic gating in ion channels.
abstract: Biological ion channels are nanoscale transmembrane pores. When water and ions are enclosed within the narrow confines of a sub-nanometer hydrophobic pore, they exhibit behavior not evident from macroscopic descriptions. At this nanoscopic level, the unfavorable interaction between the lining of a hydrophobic pore and water may lead to stochastic liquid-vapor transitions. These transient vapor states are "dewetted", i.e. effectively devoid of water molecules within all or part of the pore, thus leading to an energetic barrier to ion conduction. This process, termed "hydrophobic gating", was first observed in molecular dynamics simulations of model nanopores, where the principles underlying hydrophobic gating (i.e., changes in diameter, polarity, or transmembrane voltage) have now been extensively validated. Computational, structural, and functional studies now indicate that biological ion channels may also exploit hydrophobic gating to regulate ion flow within their pores. Here we review the evidence for this process and propose that this unusual behavior of water represents an increasingly important element in understanding the relationship between ion channel structure and function.
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 2JD, UK.
authors.forename: Prafulla
authors.initials: P
authors.lastname: Aryal
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 2JD, UK. Electronic address: mark.sansom@bioch.ox.ac.uk.
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 2JD, UK. Electronic address: stephen.tucker@physics.ox.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
mesh_terms: D000818:Animals; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology*; D008958:Models, Molecular
chemical_list: D007473:Ion Channels
keywords: K2P channel; hydrophobic gating; ion channel; nanopore; potassium channel
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7063-8
references.pmid: 12740433
references.citation: J Am Chem Soc. 2004 Nov 17;126(45):14694-5
references.pmid: 15535674
references.citation: Physiol Rev. 2010 Apr;90(2):559-605
references.pmid: 20393194
references.citation: Trends Microbiol. 1999 Oct;7(10):420-4
references.pmid: 10498951
references.citation: Phys Biol. 2006 Jul 07;3(2):147-59
references.pmid: 16829701
references.citation: Nature. 1995 Jan 5;373(6509):37-43
references.pmid: 7800037
references.citation: Nature. 2002 May 30;417(6888):515-22
references.pmid: 12037559
references.citation: Biochim Biophys Acta. 2015 Mar;1850(3):511-23
references.pmid: 24836522
references.citation: J Gen Physiol. 1965 May;48:859-72
references.pmid: 14324992
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3310-4
references.pmid: 18287006
references.citation: Nat Commun. 2014 Jul 08;5:4377
references.pmid: 25001086
references.citation: Biochim Biophys Acta. 2012 Feb;1818(2):272-85
references.pmid: 21958666
references.citation: Nature. 1986 Sep 4-10;323(6083):36-9
references.pmid: 2427958
references.citation: Biophys J. 1999 Oct;77(4):1960-72
references.pmid: 10512816
references.citation: Science. 2012 Jan 27;335(6067):436-41
references.pmid: 22282805
references.citation: Nature. 2014 Jan 2;505(7481):56-61
references.pmid: 24270805
references.citation: Biophys J. 2004 Nov;87(5):3050-65
references.pmid: 15339798
references.citation: J Chem Phys. 2004 Mar 15;120(11):5001-4
references.pmid: 15267365
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17332-7
references.pmid: 24101457
references.citation: Structure. 2010 Jul 14;18(7):839-46
references.pmid: 20637420
references.citation: J Gen Physiol. 2007 Dec;130(6):601-10
references.pmid: 17998394
references.citation: J Gen Physiol. 2010 Nov;136(5):569-79
references.pmid: 20937694
references.citation: Nat Nanotechnol. 2011 Oct 30;6(12):798-802
references.pmid: 22036811
references.citation: EMBO J. 2003 Jan 2;22(1):36-46
references.pmid: 12505982
references.citation: Biophys J. 2008 Jun;94(11):4282-98
references.pmid: 18234836
references.citation: Nat Struct Mol Biol. 2009 Jan;16(1):71-9
references.pmid: 19098918
references.citation: Nature. 2011 Jul 10;475(7356):353-8
references.pmid: 21743477
references.citation: Nature. 2008 Mar 20;452(7185):375-9
references.pmid: 18322461
references.citation: Nature. 2001 Nov 8;414(6860):188-90
references.pmid: 11700553
references.citation: Structure. 2011 Oct 12;19(10):1356-69
references.pmid: 22000509
references.citation: Eur Biophys J. 2009 Dec;39(1):61-73
references.pmid: 19404634
references.citation: Science. 2012 Jan 27;335(6067):432-6
references.pmid: 22282804
references.citation: Nature. 2002 May 30;417(6888):523-6
references.pmid: 12037560
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6275-80
references.pmid: 20308576
references.citation: J Mol Biol. 2011 Aug 5;411(1):27-35
references.pmid: 21554888
references.citation: Nature. 2003 Jun 26;423(6943):949-55
references.pmid: 12827192
references.citation: Biophys J. 2012 Jul 18;103(2):219-27
references.pmid: 22853899
references.citation: Science. 2012 Apr 13;336(6078):229-33
references.pmid: 22499946
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11471-5
references.pmid: 9736761
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):12944-9
references.pmid: 22826215
references.citation: Nature. 2009 Jan 1;457(7225):115-8
references.pmid: 18987630
references.citation: PLoS Biol. 2011 Jun;9(6):e1001101
references.pmid: 21713033
references.citation: J Phys Condens Matter. 2010 Nov 17;22(45):454120
references.pmid: 21339607
references.citation: Biochemistry. 2013 Aug 27;52(34):5708-22
references.pmid: 23947546
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5833-8
references.pmid: 20231479
references.citation: Theor Chem Acc. 2009 Sep;124(1-2):11-28
references.pmid: 20577578
references.citation: Nature. 2009 Jan 1;457(7225):111-4
references.pmid: 18987633
references.citation: Biochem J. 2013 May 1;451(3):365-74
references.pmid: 23425532
references.citation: J Gen Physiol. 2012 Mar;139(3):235-44
references.pmid: 22371364
references.citation: Nat Struct Mol Biol. 2010 Aug;17(8):1019-23
references.pmid: 20676101
references.citation: Structure. 2005 Apr;13(4):591-600
references.pmid: 15837197
references.citation: EMBO J. 2011 Aug 05;30(17):3607-19
references.pmid: 21822218
references.citation: FEBS Lett. 2003 Nov 27;555(1):85-90
references.pmid: 14630324
references.citation: Biophys J. 2011 Aug 17;101(4):809-17
references.pmid: 21843471
references.citation: Science. 2008 Aug 29;321(5893):1179-83
references.pmid: 18755969
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19814-9
references.pmid: 21041674
references.citation: J Biol Chem. 2013 Dec 6;288(49):35081-92
references.pmid: 24163367
references.citation: EMBO J. 2012 Aug 1;31(15):3297-308
references.pmid: 22728824
references.citation: Annu Rev Microbiol. 2010;64:313-29
references.pmid: 20825352
references.citation: Biophys J. 2004 May;86(5):2883-95
references.pmid: 15111405
references.citation: Nature. 2011 Jun 2;474(7349):54-60
references.pmid: 21572436
references.citation: Science. 2002 Nov 22;298(5598):1582-7
references.pmid: 12446901
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):966-71
references.pmid: 24367074
references.citation: Science. 1998 Apr 3;280(5360):69-77
references.pmid: 9525859
references.citation: J Neurosci. 2012 Oct 10;32(41):14064-73
references.pmid: 23055474
references.citation: Acc Chem Res. 2013 Dec 17;46(12):2834-46
references.pmid: 23713693