Proton transport behavior through the influenza A M2 channel: insights from molecular simulation.
The structural properties of the influenza A virus M2 transmembrane channel in dimyristoylphosphatidylcholine bilayer for each of the four protonation states of the proton-gating His-37 tetrad and their effects on proton transport for this low-pH activated, highly proton-selective channel are studied by classical molecular dynamics with the multistate empirical valence-bond (MS-EVB) methodology. The excess proton permeation free energy profile and maximum ion conductance calculated from the MS-EVB simulation data combined with the Poisson-Nernst-Planck theory indicates that the triply protonated His-37 state is the most likely open state via a significant side-chain conformational change of the His-37 tetrad. This proposed open state of M2 has a calculated proton permeation free energy barrier of 7 kcal/mol and a maximum conductance of 53 pS compared to the experimental value of 6 pS. By contrast, the maximum conductance for Na(+) is calculated to be four orders of magnitude lower, in reasonable agreement with the experimentally observed proton selectivity. The pH value to activate the channel opening is estimated to be 5.5 from dielectric continuum theory, which is also consistent with experimental results. This study further reveals that the Ala-29 residue region is the primary binding site for the antiflu drug amantadine (AMT), probably because that domain is relatively spacious and hydrophobic. The presence of AMT is calculated to reduce the proton conductance by 99.8% due to a significant dehydration penalty of the excess proton in the vicinity of the channel-bound AMT.
Chen
Hanning
H
Center for Biophysical Modeling and Simulation, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112-0850, USA.
Wu
Yujie
Y
Voth
Gregory A
GA
D000409:Alanine / Q000737:chemistry; D001665:Binding Sites; D001692:Biological Transport; D001703:Biophysics / Q000379:methods*; D003198:Computer Simulation; D004553:Electric Conductivity; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D016012:Poisson Distribution; D011485:Protein Binding; D011522:Protons; D012964:Sodium / Q000737:chemistry
D011522:Protons; D006639:Histidine; D012964:Sodium; D000409:Alanine
J Mol Graph. 1996 Jun;14(3):136-41
8901641
J Mol Biol. 2005 Mar 18;347(1):169-79
15733926
J Mol Graph Model. 2006 Oct;25(2):247-60
16458552
Biophys J. 2002 Jun;82(6):2833-46
12023208
Cell. 1991 Oct 4;67(1):117-30
1913813
Biophys J. 2000 Jan;78(1):55-69
10620273
Biophys J. 2005 Oct;89(4):2402-11
16040757
Biophys J. 2002 Mar;82(3):1460-8
11867461
Biophys J. 1996 Mar;70(3):1335-46
8785289
J Gen Virol. 1994 Dec;75 ( Pt 12):3477-84
7527837
Trends Microbiol. 1995 Jul;3(7):271
7551640
Biochemistry. 1990 Nov 6;29(44):10219-25
2271649
Virology. 1994 Jul;202(1):287-93
7516598
J Physiol. 1996 Jul 15;494 ( Pt 2):329-36
8841994
Virology. 1992 Sep;190(1):11-8
1529523
Protein Sci. 2001 Nov;10(11):2241-50
11604531
Biophys J. 2006 Nov 1;91(9):3162-9
16877513
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6865-70
16632600
Biophys J. 2004 Sep;87(3):1697-704
15345548
Biophys J. 2000 Aug;79(2):767-75
10920010
J Physiol. 2003 Jan 15;546(Pt 2):427-38
12527729
Biophys J. 1999 Feb;76(2):642-56
9929470
J Virol. 1993 Sep;67(9):5585-94
7688826
Virology. 1991 Jul;183(1):32-43
2053285
J Biol Chem. 2006 Apr 7;281(14):8997-9000
16407184
J Biol Chem. 2002 Oct 18;277(42):39880-6
12183461
Biophys J. 2002 Oct;83(4):1987-96
12324417
Phys Rev A Gen Phys. 1985 Mar;31(3):1695-1697
9895674
Protein Sci. 2003 Nov;12(11):2597-605
14573870
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11301-6
9326604
Biophys J. 2007 Jun 15;92(12):4335-43
17384070
Dev Cell. 2003 Jul;5(1):175-84
12852861
Virology. 1991 Feb;180(2):617-24
1989386
FEBS Lett. 2003 Sep 18;552(1):17-22
12972146
Biophys J. 2004 Oct;87(4):2299-309
15454431
Biophys J. 1993 Dec;65(6):2455-60
7508762
Cell. 1992 May 1;69(3):517-28
1374685
Cell. 1985 Mar;40(3):627-33
3882238
Biophys J. 2006 May 15;90(10):3447-68
16500984
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19766-70
17172452
Biophys J. 2000 Dec;79(6):3139-43
11106618
Structure. 2005 Dec;13(12):1789-98
16338407
FEBS Lett. 2000 May 12;473(2):195-8
10812073
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W368-71
15980491
Protein Sci. 2005 Apr;14(4):856-61
15741338
Physiol Rev. 2003 Apr;83(2):475-579
12663866
Biochemistry. 1989 Apr 4;28(7):2936-40
2545240
Virology. 1999 Feb 1;254(1):196-209
9927586
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
8744570
J Virol. 1994 Feb;68(2):911-9
7507186
Biochemistry. 1993 Mar 30;32(12):2942-6
8384483
Biophys J. 2007 Jan 1;92(1):61-9
17056732
Biophys J. 2002 Feb;82(2):1068-75
11806946
J Phys Chem B. 2007 May 3;111(17):4300-14
17429993
Biophys J. 2007 Jan 1;92(1):46-60
17056733
J Mol Biol. 1999 Feb 26;286(3):951-62
10024461
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14772-7
14657351
J Biol Chem. 2000 Oct 6;275(40):31038-50
10913133
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):117-22
14691245
FEBS Lett. 2003 Sep 18;552(1):23-7
12972147
Biophys J. 1998 Sep;75(3):1211-22
9726923
J Biol Chem. 2005 Jun 3;280(22):21463-72
15784624
Biophys J. 2006 May 15;90(10):L73-5
16581846
Biophys J. 1995 Oct;69(4):1363-71
8534806
Virology. 1992 Sep;190(1):485-9
1382343
J Virol. 2001 Apr;75(8):3647-56
11264354
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6795-800
15857953
Biochemistry. 2001 May 22;40(20):6053-60
11352741
Biophys J. 1991 Feb;59(2):271-7
1706949
Virology. 1997 Jun 23;233(1):163-73
9201226
J Phys Chem B. 2008 Jan 17;112(2):467-82
17999484
Virology. 1981 Jul 30;112(2):746-51
7257189
Biochemistry. 2002 Nov 5;41(44):13170-7
12403618
Methods Enzymol. 1999;294:490-506
9916245
Biochim Biophys Acta. 1978 Sep 21;505(1):1-44
708723
Cell. 1992 May 15;69(4):577-8
1375129