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. 2002 Sep;83(3):1501–1510. doi: 10.1016/S0006-3495(02)73920-9

Molecular dynamics simulation of the evolution of hydrophobic defects in one monolayer of a phosphatidylcholine bilayer: relevance for membrane fusion mechanisms.

D Peter Tieleman 1, Joe Bentz 1
PMCID: PMC1302248  PMID: 12202375

Abstract

The spontaneous formation of the phospholipid bilayer underlies the permeability barrier function of the biological membrane. Tears or defects that expose water to the acyl chains are spontaneously healed by lipid lateral diffusion. However, mechanical barriers, e.g., protein aggregates held in place, could sustain hydrophobic defects. Such defects have been postulated to occur in processes such as membrane fusion. This gives rise to a new question in bilayer structure: What do the lipids do in the absence of lipid lateral diffusion to minimize the free energy of a hydrophobic defect? As a first step to understand this rather fundamental question about bilayer structure, we performed molecular dynamic simulations of up to 10 ns of a planar bilayer from which lipids have been deleted randomly from one monolayer. In one set of simulations, approximately one-half of the lipids in the defect monolayer were restrained to form a mechanical barrier. In the second set, lipids were free to diffuse around. The question was simply whether the defects caused by removing a lipid would aggregate together, forming a large hydrophobic cavity, or whether the membrane would adjust in another way. When there are no mechanical barriers, the lipids in the defect monolayer simply spread out and thin with little effect on the other intact monolayer. In the presence of a mechanical barrier, the behavior of the lipids depends on the size of the defect. When 3 of 64 lipids are removed, the remaining lipids adjust the lower one-half of their chains, but the headgroup structure changes little and the intact monolayer is unaffected. When 6 to 12 lipids are removed, the defect monolayer thins, lipid disorder increases, and lipids from the intact monolayer move toward the defect monolayer. Whereas this is a highly simplified model of a fusion site, this engagement of the intact monolayer into the fusion defect is strikingly consistent with recent results for influenza hemagglutinin mediated fusion.

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Selected References

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  1. Armstrong R. T., Kushnir A. S., White J. M. The transmembrane domain of influenza hemagglutinin exhibits a stringent length requirement to support the hemifusion to fusion transition. J Cell Biol. 2000 Oct 16;151(2):425–437. doi: 10.1083/jcb.151.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bentz J. Membrane fusion mediated by coiled coils: a hypothesis. Biophys J. 2000 Feb;78(2):886–900. doi: 10.1016/S0006-3495(00)76646-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bentz J. Minimal aggregate size and minimal fusion unit for the first fusion pore of influenza hemagglutinin-mediated membrane fusion. Biophys J. 2000 Jan;78(1):227–245. doi: 10.1016/S0006-3495(00)76587-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bentz J., Mittal A. Deployment of membrane fusion protein domains during fusion. Cell Biol Int. 2000;24(11):819–838. doi: 10.1006/cbir.2000.0632. [DOI] [PubMed] [Google Scholar]
  5. Berger O., Edholm O., Jähnig F. Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys J. 1997 May;72(5):2002–2013. doi: 10.1016/S0006-3495(97)78845-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chernomordik L. V., Frolov V. A., Leikina E., Bronk P., Zimmerberg J. The pathway of membrane fusion catalyzed by influenza hemagglutinin: restriction of lipids, hemifusion, and lipidic fusion pore formation. J Cell Biol. 1998 Mar 23;140(6):1369–1382. doi: 10.1083/jcb.140.6.1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chernomordik L. Non-bilayer lipids and biological fusion intermediates. Chem Phys Lipids. 1996 Jul 15;81(2):203–213. doi: 10.1016/0009-3084(96)02583-2. [DOI] [PubMed] [Google Scholar]
  8. Eckert D. M., Kim P. S. Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem. 2001;70:777–810. doi: 10.1146/annurev.biochem.70.1.777. [DOI] [PubMed] [Google Scholar]
  9. Kim C. H., Macosko J. C., Shin Y. K. The mechanism for low-pH-induced clustering of phospholipid vesicles carrying the HA2 ectodomain of influenza hemagglutinin. Biochemistry. 1998 Jan 6;37(1):137–144. doi: 10.1021/bi971982w. [DOI] [PubMed] [Google Scholar]
  10. Kozlov M. M., Chernomordik L. V. A mechanism of protein-mediated fusion: coupling between refolding of the influenza hemagglutinin and lipid rearrangements. Biophys J. 1998 Sep;75(3):1384–1396. doi: 10.1016/S0006-3495(98)74056-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kozlovsky Yonathan, Kozlov Michael M. Stalk model of membrane fusion: solution of energy crisis. Biophys J. 2002 Feb;82(2):882–895. doi: 10.1016/S0006-3495(02)75450-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kuzmin P. I., Zimmerberg J., Chizmadzhev Y. A., Cohen F. S. A quantitative model for membrane fusion based on low-energy intermediates. Proc Natl Acad Sci U S A. 2001 Jun 12;98(13):7235–7240. doi: 10.1073/pnas.121191898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Leikina E., LeDuc D. L., Macosko J. C., Epand R., Epand R., Shin Y. K., Chernomordik L. V. The 1-127 HA2 construct of influenza virus hemagglutinin induces cell-cell hemifusion. Biochemistry. 2001 Jul 27;40(28):8378–8386. doi: 10.1021/bi010466+. [DOI] [PubMed] [Google Scholar]
  14. Lentz B. R., Lee J. K. Poly(ethylene glycol) (PEG)-mediated fusion between pure lipid bilayers: a mechanism in common with viral fusion and secretory vesicle release? Mol Membr Biol. 1999 Oct-Nov;16(4):279–296. doi: 10.1080/096876899294508. [DOI] [PubMed] [Google Scholar]
  15. Markin Vladislav S., Albanesi Joseph P. Membrane fusion: stalk model revisited. Biophys J. 2002 Feb;82(2):693–712. doi: 10.1016/S0006-3495(02)75432-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Marrink S. J., Lindahl E., Edholm O., Mark A. E. Simulation of the spontaneous aggregation of phospholipids into bilayers. J Am Chem Soc. 2001 Sep 5;123(35):8638–8639. doi: 10.1021/ja0159618. [DOI] [PubMed] [Google Scholar]
  17. Melikyan G. B., Lin S., Roth M. G., Cohen F. S. Amino acid sequence requirements of the transmembrane and cytoplasmic domains of influenza virus hemagglutinin for viable membrane fusion. Mol Biol Cell. 1999 Jun;10(6):1821–1836. doi: 10.1091/mbc.10.6.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mittal A., Bentz J. Comprehensive kinetic analysis of influenza hemagglutinin-mediated membrane fusion: role of sialate binding. Biophys J. 2001 Sep;81(3):1521–1535. doi: 10.1016/S0006-3495(01)75806-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mittal Aditya, Leikina Eugenia, Bentz Joe, Chernomordik Leonid V. Kinetics of influenza hemagglutinin-mediated membrane fusion as a function of technique. Anal Biochem. 2002 Apr 15;303(2):145–152. doi: 10.1006/abio.2002.5590. [DOI] [PubMed] [Google Scholar]
  20. Moore P. B., Lopez C. F., Klein M. L. Dynamical properties of a hydrated lipid bilayer from a multinanosecond molecular dynamics simulation. Biophys J. 2001 Nov;81(5):2484–2494. doi: 10.1016/S0006-3495(01)75894-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nagle J. F., Zhang R., Tristram-Nagle S., Sun W., Petrache H. I., Suter R. M. X-ray structure determination of fully hydrated L alpha phase dipalmitoylphosphatidylcholine bilayers. Biophys J. 1996 Mar;70(3):1419–1431. doi: 10.1016/S0006-3495(96)79701-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Qiao H., Armstrong R. T., Melikyan G. B., Cohen F. S., White J. M. A specific point mutant at position 1 of the influenza hemagglutinin fusion peptide displays a hemifusion phenotype. Mol Biol Cell. 1999 Aug;10(8):2759–2769. doi: 10.1091/mbc.10.8.2759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Qiao H., Pelletier S. L., Hoffman L., Hacker J., Armstrong R. T., White J. M. Specific single or double proline substitutions in the "spring-loaded" coiled-coil region of the influenza hemagglutinin impair or abolish membrane fusion activity. J Cell Biol. 1998 Jun 15;141(6):1335–1347. doi: 10.1083/jcb.141.6.1335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Siegel D. P. The modified stalk mechanism of lamellar/inverted phase transitions and its implications for membrane fusion. Biophys J. 1999 Jan;76(1 Pt 1):291–313. doi: 10.1016/S0006-3495(99)77197-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Skehel J. J., Wiley D. C. Coiled coils in both intracellular vesicle and viral membrane fusion. Cell. 1998 Dec 23;95(7):871–874. doi: 10.1016/s0092-8674(00)81710-9. [DOI] [PubMed] [Google Scholar]
  26. Tieleman D. P., Berendsen H. J., Sansom M. S. An alamethicin channel in a lipid bilayer: molecular dynamics simulations. Biophys J. 1999 Apr;76(4):1757–1769. doi: 10.1016/s0006-3495(99)77337-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tieleman D. P., Marrink S. J., Berendsen H. J. A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems. Biochim Biophys Acta. 1997 Nov 21;1331(3):235–270. doi: 10.1016/s0304-4157(97)00008-7. [DOI] [PubMed] [Google Scholar]

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