Membrane insertion of a voltage sensor helix.
Most membrane proteins contain a transmembrane (TM) domain made up of a bundle of lipid-bilayer-spanning α-helices. TM α-helices are generally composed of a core of largely hydrophobic amino acids, with basic and aromatic amino acids at each end of the helix forming interactions with the lipid headgroups and water. In contrast, the S4 helix of ion channel voltage sensor (VS) domains contains four or five basic (largely arginine) side chains along its length and yet adopts a TM orientation as part of an independently stable VS domain. Multiscale molecular dynamics simulations are used to explore how a charged TM S4 α-helix may be stabilized in a lipid bilayer, which is of relevance in the context of mechanisms of translocon-mediated insertion of S4. Free-energy profiles for insertion of the S4 helix into a phospholipid bilayer suggest that it is thermodynamically favorable for S4 to insert from water to the center of the membrane, where the helix adopts a TM orientation. This is consistent with crystal structures of Kv channels, biophysical studies of isolated VS domains in lipid bilayers, and studies of translocon-mediated S4 helix insertion. Decomposition of the free-energy profiles reveals the underlying physical basis for TM stability, whereby the preference of the hydrophobic residues of S4 to enter the bilayer dominates over the free-energy penalty for inserting charged residues, accompanied by local distortion of the bilayer and penetration of waters. We show that the unique combination of charged and hydrophobic residues in S4 allows it to insert stably into the membrane.
Department of Biochemistry, University of Oxford, United Kingdom.
Chze Ling
CL
Wee
Alan
A
Chetwynd
Mark S P
MS
Sansom
D003198:Computer Simulation; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010743:Phospholipids / Q000737:chemistry; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
D007473:Ion Channels; D008051:Lipid Bilayers; D008565:Membrane Proteins; D010743:Phospholipids; D014867:Water
Biophys J. 2010 Jun 16;98(12):2857-66
20550898
Trends Biochem Sci. 2000 Sep;25(9):429-34
10973056
Curr Opin Struct Biol. 2005 Apr;15(2):144-50
15837171
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2631-6
17301243
Nature. 2007 Nov 15;450(7168):376-82
18004376
Biochemistry. 2008 Oct 28;47(43):11321-31
18831536
J Chem Theory Comput. 2008 May;4(5):819-34
26621095
Curr Opin Struct Biol. 2007 Apr;17(2):192-8
17383173
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15684-9
19805218
J Phys Chem B. 2005 Feb 24;109(7):2469-73
16851243
Biophys J. 1999 Oct;77(4):2102-13
10512830
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4943-8
17360368
Science. 2005 Aug 5;309(5736):897-903
16002581
Biophys J. 1998 Feb;74(2 Pt 1):931-43
9533704
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15059-64
16217012
Structure. 2007 Feb;15(2):235-44
17292841
J Mol Biol. 1993 Dec 5;234(3):779-815
8254673
Nature. 2008 Dec 18;456(7224):891-7
19092925
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19276-81
19050073
Nat Struct Mol Biol. 2010 Jul;17(7):869-875
20543828
J Am Chem Soc. 2009 Feb 18;131(6):2107-9
19175309
Trends Pharmacol Sci. 2001 Jan;22(1):23-6
11165668
Science. 2005 Mar 4;307(5714):1427
15681341
Biophys J. 1997 May;72(5):2002-13
9129804
J Phys Chem B. 2006 Mar 2;110(8):3674-84
16494423
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8263-8
17488813
Nature. 1969 Mar 1;221(5183):844-6
5765058
Annu Rev Biophys Biomol Struct. 1999;28:319-65
10410805
Biophys J. 2006 May 1;90(9):L64-6
16533847
Nature. 2008 Feb 14;451(7180):826-9
18273018
Nature. 2006 Dec 7;444(7120):775-9
17136096
J Mol Biol. 2009 Apr 17;387(5):1153-64
19236881
J Chem Theory Comput. 2010 Mar 9;6(3):966-76
26613320
Nature. 2009 Nov 26;462(7272):473-9
19940918
Nature. 2003 May 1;423(6935):33-41
12721618
J Mol Biol. 2009 Jul 31;390(5):902-12
19481093
Biophys J. 2007 Nov 1;93(9):3070-82
17704179
Biophys J. 2010 Jun 16;98(12):L60-2
20550886
J Gen Physiol. 2007 Aug;130(2):237-40
17635964
Methods Mol Biol. 2000;143:97-129
11084904
J Phys Chem B. 2010 Jan 21;114(2):826-39
20028006
Biophys J. 2008 Apr 15;94(8):L61-3
18199662
Nature. 2005 Jan 27;433(7024):377-81
15674282
Biophys J. 2008 Oct;95(7):3161-73
18586841
J Phys Chem B. 2008 Aug 14;112(32):9588-602
18636764
J Am Chem Soc. 2010 Apr 28;132(16):5803-11
20373735
Proteins. 2005 Sep 1;60(4):606-16
16028222
J Mol Biol. 1999 Aug 27;291(4):965-76
10452900
J Phys Chem B. 2008 Mar 20;112(11):3277-82
18293960
Biophys J. 2006 Dec 1;91(11):L90-2
17012321
Biophys J. 2007 Nov 15;93(10):3470-9
17693473
Annu Rev Biophys. 2008;37:23-42
18573071
Phys Rev Lett. 2008 Jan 11;100(1):018103
18232823
Biophys J. 2008 Aug;95(4):1729-44
18487312
Proteins. 2005 Jun 1;59(4):773-82
15815975
Biophys J. 2008 May 1;94(9):3393-404
18212019