title: The effect of sterols on amphotericin B self-aggregation in a lipid bilayer as revealed by free energy simulations.
abstract: Amphotericin B (AmB) is an effective but toxic antifungal drug, known to increase the permeability of the cell membrane, presumably by assembling into transmembrane pores in a sterol-dependent manner. The aggregation of AmB molecules in a phospholipid bilayer is, thus, crucial for the drug's activity. To provide an insight into the molecular nature of this process, here, we report an atomistic molecular dynamics simulation study of AmB head-to-head dimerization in a phospholipid bilayer, a possible early stage of aggregation. To compare the effect of sterols on the thermodynamics of aggregation and the architecture of the resulting AmB-AmB complexes, free energy profiles for the dimerization in ergosterol- or cholesterol-containing and sterol-free membranes are derived from the simulations. These profiles demonstrate that although AmB dimers are formed in all the systems studied, they are significantly less favorable in the bilayer with ergosterol than in the cholesterol-containing or sterol-free ones. We investigate the structural and energetic determinants of this difference and discuss its consequences for the AmB mechanism of action.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Neumann
authors.forename: Maciej
authors.initials: M
authors.lastname: Baginski
authors.forename: Szymon
authors.initials: S
authors.lastname: Winczewski
authors.forename: Jacek
authors.initials: J
authors.lastname: Czub
mesh_terms: D000666:Amphotericin B / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002784:Cholesterol / Q000494:pharmacology*; D019281:Dimerization; D004875:Ergosterol / Q000494:pharmacology*; D008051:Lipid Bilayers / Q000737:chemistry*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010743:Phospholipids / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D008051:Lipid Bilayers; D010743:Phospholipids; D000666:Amphotericin B; D002784:Cholesterol; D004875:Ergosterol
references.citation: Biochim Biophys Acta. 2000 Nov 10;1469(3):159-95
references.pmid: 11063882
references.citation: Biochim Biophys Acta. 2007 Oct;1768(10):2616-26
references.pmid: 17662232
references.citation: Biochemistry. 1997 Apr 22;36(16):4959-68
references.pmid: 9125518
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2009 Aug;80(2 Pt 1):021931
references.pmid: 19792175
references.citation: PLoS One. 2012;7(9):e45135
references.pmid: 23028805
references.citation: Biochim Biophys Acta. 1998 Oct 15;1375(1-2):43-51
references.pmid: 9767100
references.citation: J Comput Chem. 2005 Oct;26(13):1383-99
references.pmid: 16028234
references.citation: Biochemistry. 1978 Jan 24;17(2):381-4
references.pmid: 619997
references.citation: J Am Chem Soc. 2005 Aug 3;127(30):10667-75
references.pmid: 16045354
references.citation: J Chem Phys. 2004 Aug 15;121(7):2904-14
references.pmid: 15291601
references.citation: Biophys J. 2002 Dec;83(6):3245-55
references.pmid: 12496093
references.citation: Biophys Chem. 1981 Dec;14(4):325-32
references.pmid: 6279197
references.citation: Acc Chem Res. 2002 Jun;35(6):438-46
references.pmid: 12069629
references.citation: J Photochem Photobiol B. 2003 Jan;69(1):49-57
references.pmid: 12547496
references.citation: Mol Pharmacol. 1986 Mar;29(3):293-8
references.pmid: 3951434
references.citation: J Am Chem Soc. 2010 Dec 29;132(51):18266-72
references.pmid: 21126070
references.citation: J Am Chem Soc. 2009 Aug 26;131(33):11855-60
references.pmid: 19645473
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6733-8
references.pmid: 21368185
references.citation: Drugs. 2009;69(3):361-92
references.pmid: 19275278
references.citation: Biophys J. 2007 Jun 1;92(11):3960-7
references.pmid: 17369407
references.citation: J Mol Biol. 1983 May 15;166(2):211-7
references.pmid: 6854644
references.citation: Biochim Biophys Acta. 1988 Oct 20;944(3):477-86
references.pmid: 3179301
references.citation: Biophys J. 2004 Nov;87(5):3264-76
references.pmid: 15315952
references.citation: Biochemistry. 1991 Jun 11;30(23):5707-15
references.pmid: 2043613
references.citation: Biochim Biophys Acta. 1995 Sep 13;1238(2):163-76
references.pmid: 7548131
references.citation: J Chem Phys. 2004 Feb 22;120(8):3563-78
references.pmid: 15268518
references.citation: Biophys Chem. 2009 Apr;141(1):105-16
references.pmid: 19185412
references.citation: PLoS One. 2012;7(1):e30261
references.pmid: 22276169
references.citation: Biophys J. 2005 Mar;88(3):1799-808
references.pmid: 15596499
references.citation: Curr Drug Metab. 2009 Jun;10(5):459-69
references.pmid: 19689243
references.citation: Biochemistry. 2005 Jan 18;44(2):704-10
references.pmid: 15641796
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2234-9
references.pmid: 22308411
references.citation: Biophys Chem. 1996 Jan;57(2-3):205-17
references.pmid: 8573677
references.citation: Trends Pharmacol Sci. 1996 Dec;17(12):445-9
references.pmid: 9014498
references.citation: Biochim Biophys Acta. 1984 Oct 3;776(2):317-29
references.pmid: 6477913
references.citation: Biochim Biophys Acta. 2000 Feb 15;1463(2):323-32
references.pmid: 10675510
references.citation: J Am Chem Soc. 1971 Sep 8;93(18):4560-4
references.pmid: 5131155
references.citation: Biochim Biophys Acta. 1995 Dec 13;1240(2):179-95
references.pmid: 8541289
references.citation: Biochim Biophys Acta. 2010 Nov;1798(11):2124-30
references.pmid: 20699086
references.citation: Biochim Biophys Acta. 1974 Feb 26;339(1):57-70
references.pmid: 4546885
references.citation: Int J Antimicrob Agents. 2001 Mar;17(3):161-9
references.pmid: 11282260
references.citation: Biochim Biophys Acta. 1986 Dec 22;864(3-4):257-304
references.pmid: 3539192
references.citation: Biophys J. 2006 Apr 1;90(7):2368-82
references.pmid: 16399829
references.citation: J Phys Chem B. 2009 Dec 3;113(48):15875-85
references.pmid: 19929013
references.citation: Biochemistry. 2008 Dec 23;47(51):13463-9
references.pmid: 19053254
references.citation: J Antibiot (Tokyo). 2007 Jul;60(7):436-46
references.pmid: 17721002
references.citation: Biochim Biophys Acta. 2001 Sep 3;1528(1):15-24
references.pmid: 11514093
references.citation: J Phys Chem B. 2010 Jun 17;114(23):7830-43
references.pmid: 20496934
references.citation: J Phys Chem B. 2006 Aug 24;110(33):16743-53
references.pmid: 16913814
references.citation: Biochim Biophys Acta. 2002 Dec 23;1567(1-2):63-78
references.pmid: 12488039
references.citation: Biophys J. 2002 Mar;82(3):1429-44
references.pmid: 11867458
references.citation: Chem Phys Lipids. 2008 Jan;151(1):41-50
references.pmid: 17963699
references.citation: Biophys J. 2003 Oct;85(4):2323-32
references.pmid: 14507696
references.citation: Bioorg Med Chem. 2012 Oct 1;20(19):5699-704
references.pmid: 22959766
references.citation: Farmaco. 2000 Mar;55(3):206-8
references.pmid: 10919084
references.citation: Biochemistry. 1983 Jun 7;22(12):2939-44
references.pmid: 6871175