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Molecular dynamics study of homo-oligomeric ion channels: Structures of the surrounding lipids and dynamics of water movement

Department of Chemistry & Biochemistry and the West Center for Computational Chemistry and Drug Design, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104, USA

Topical Section: Membrane biophysics

Molecular dynamics simulations were used to study the structural perturbations of lipids surrounding transmembrane ion channel forming helices/helical bundles and the movement of water within the pores of the ion-channels/bundles. Specifically, helical monomers to hexameric helical bundles embedded in palmitoyl-oleoyl-phosphatidyl-choline (POPC) lipid bilayer were studied. Two amphipathic α-helices with the sequence Ac-(LSLLLSL)3-NH2 (LS2), and Ac-(LSSLLSL)3-NH2 (LS3), which are known to form ion channels, were used. To investigate the surrounding lipid environment, we examined the hydrophobic mismatch, acyl chain order parameter profiles, lipid head-to-tail vector projection on the membrane surface, and the lipid headgroup vector projection. We find that the lipid structure is perturbed within approximately two lipid solvation shells from the protein bundle for each system (~15.0 Å). Beyond two lipid “solvation” shells bulk lipid bilayer properties were observed in all systems. To understand water flow, we enumerated each time a water molecule enters or exited the channel, which allowed us to calculate the number of water crossing events and their rates, and the residence time of water in the channel. We correlate the rate of water crossing with the structural properties of these ion channels and find that the movements of water are predominantly governed by the packing and pore diameter, rather than the topology of each peptide or the pore (hydrophobic or hydrophilic). We show that the crossing events of water fit quantitatively to a stochastic process and that water molecules are traveling diffusively through the pores. These lipid and water findings can be used for understanding the environment within and around ion channels. Furthermore, these findings can benefit various research areas such as rational design of novel therapeutics, in which the drug interacts with membranes and transmembrane proteins to enhance the efficacy or reduce off-target effects.
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Keywords ion channels; water flux; lipid perturbations; membranes; helical bundles

Citation: Thuy Hien Nguyen, Catherine C. Moore, Preston B. Moore, Zhiwei Liu. Molecular dynamics study of homo-oligomeric ion channels: Structures of the surrounding lipids and dynamics of water movement. AIMS Biophysics, 2018, 5(1): 50-76. doi: 10.3934/biophy.2018.1.50


  • 1. Lee AG (2004) How lipids affect the activities of integral membrane proteins. BBA-Biomembranes 1666: 62–87.    
  • 2. Pohorille A, Schweighofer K, Wilson MA (2006) The origin and early evolution of membrane channels. Astrobiology 5: 1–17.    
  • 3. Hille B (2001) Ion Channels of Excitable Membranes, 3 Eds., Sinauer.
  • 4. Kaczorowski GJ, Mcmanus OB, Priest BT, et al. (2008) Ion channels as drug targets: The next GPCRs. J Gen Physiol 131: 399–405.    
  • 5. Ackerman MJ, Clapham DE (1997) Ion channels-basic science and clinical disease. N Engl J Med 336: 1575–1586.    
  • 6. Lear JD, Wasserman ZR, Degrado WF (1988) Synthetic amphiphilic peptide models for protein ion channels. Science 240: 1177–1181.    
  • 7. Kienker PK, Degrado WF, Lear JD (1994) A helical-dipole model describes the single-channel current rectification of an uncharged peptide ion channel. Proc Natl Acad Sci USA 91: 4859–4863.    
  • 8. Petrache HI, Zuckerman DM, Sachs JN, et al. (2002) Hydrophobic matching mechanism investigated by molecular dynamics simulations. Langmuir 18: 1340–1351.    
  • 9. Nguyen THT, Liu Z, Moore PB (2013) Molecular dynamics simulations of homo-oligomeric bundles embedded within a lipid bilayer. Biophys J 105: 1569–1580.    
  • 10. Howard KP, Lear JD, Degrado WF (2002) Sequence determinants of the energetics of folding of a transmembrane four-helix-bundle protein. Proc Natl Acad Sci USA 99: 8568–8572.    
  • 11. Arseneault M, Dumont M, Otis F, et al. (2012) Characterization of channel-forming peptide nanostructures. Biophys Chem 162: 6–13.    
  • 12. Fischer WB (2005) Viral Membrane Proteins: Structure, Function, and Drug Design, In: Protein Rev, Kluwer Academic/Plenum Publishers.
  • 13. Wang J, Kim S, Kovacs F, et al. (2001) Structure of the transmembrane region of the M2 protein H+ channel. Protein Sci 10: 2241–2250.
  • 14. Stouffer AL, Acharya R, Salom D, et al. (2008) Structural basis for the function and inhibition of an influenza virus proton channel. Nature 451: 596–599.    
  • 15. Schnell JR, Chou JJ (2008) Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451: 591–595.    
  • 16. Kovacs FA, Cross TA (1997) Transmembrane four-helix bundle of influenza A M2 protein channel: Structural implications from helix tilt and orientation. Biophys J 73: 2511–2517.    
  • 17. Acharya R, Carnevale V, Fiorin G, et al. (2010) Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus. Proc Natl Acad Sci USA 107: 15075–15080.    
  • 18. Moore PB, Zhong Q, Husslein T, et al. (1998) Simulation of the HIV-1 Vpu transmembrane domain as a pentameric bundle. FEBS Lett 431: 143–148.    
  • 19. Woolley GA, Wallace BA (1992) Model ion channels: Gramicidin and alamethicin. J Membrane Biol 129: 109–136.
  • 20. Opella SJ, Marassi FM, Gesell JJ, et al. (1999) Structures of the M2 channel-lining segments from nicotinic acetylcholine and NMDA receptors by NMR spectroscopy. Nat Struct Mol Biol 6: 374–379.    
  • 21. Akerfeldt KS, Kienker PK, Lear JD (1996) Structure and conduction mechanisms of minimalist ion channels. Compr Supramol Chem 10: 659–686.
  • 22. Gratkowski H, Lear JD, Degrado WF (2001) Polar side chains drive the association of model transmembrane peptides. Proc Natl Acad Sci USA 98: 880–885.    
  • 23. Randa HS, Forrest LR, Voth GA, et al. (1999) Molecular dynamics of synthetic leucine-serine ion channels in a phospholipid membrane. Biophys J 77: 2400–2410.    
  • 24. Oiki S, Danho W, Madison V, et al. (1988) M2 δ, a candidate for the structure lining the ionic channel of the nicotinic cholinergic receptor. Proc Natl Acad Sci USA 85: 8703–8707.    
  • 25. Carruthers A, Melchior DL (1986) How bilayer lipids affect membrane protein activity. Trends Biochem Sci 11: 331–335.    
  • 26. Palsdottir H, Hunte C (2004) Lipids in membrane protein structures. BBA-Biomembranes 1666: 2–18.    
  • 27. Lindahl E, Sansom MSP (2008) Membrane proteins: Molecular dynamics simulations. Curr Opin Struct Biol 18: 425–431.    
  • 28. Phillips JC, Braun R, Wang W, et al. (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26: 1781–1802.    
  • 29. Duan Y, Wu C, Chowdhury S, et al. (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24: 1999–2012.    
  • 30. Hu Z, Jiang J (2010) Assessment of biomolecular force fields for molecular dynamics simulations in a protein crystal. J Comput Chem 31: 371–380.
  • 31. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An N.log(N) method for Ewald sums in large systems. J Chem Phys 98: 10089–10092.
  • 32. Feller SE, Yin D, Pastor RW, et al. (1997) Molecular dynamics simulation of unsaturated lipid bilayers at low hydration: Parameterization and comparison with diffraction studies. Biophys J 73: 2269–2279.    
  • 33. Jojart B, Martinek TA (2007) Performance of the general amber force field in modeling aqueous POPC membrane bilayers. J Comput Chem 28: 2051–2058.    
  • 34. Taylor J, Whiteford NE, Bradley G, et al. (2009) Validation of all-atom phosphatidylcholine lipid force fields in the tensionless NPT ensemble. BBA-Biomembranes 1788: 638–649.    
  • 35. Rosso L, Gould IR (2007) Structure and dynamics of phospholipid bilayers using recently developed general all-atom force fields. J Comput Chem 29: 24–37.
  • 36. Kučerka N, Tristram-Nagle S, Nagle JF (2006) Structure of fully hydrated fluid phase lipid bilayers with monounsaturated chains. J Membrane Biol 208: 193–202.    
  • 37. Nielsen SO, Ensing B, Ortiz V, et al. (2005) Lipid bilayer perturbations around a transmembrane nanotube: A coarse grain molecular dynamics study. Biophys J 88: 3822–3828.    
  • 38. De Planque MR, Killian JA (2003) Protein-lipid interactions studied with designed transmembrane peptides: Role of hydrophobic matching and interfacial anchoring (Review). Mol Membr Biol 20: 271–284.    
  • 39. Nyholm TKM, Oezdirekcan S, Killian JA (2007) How protein transmembrane segments sense the lipid environment. Biochemistry 46: 1457–1465.    
  • 40. Sonne J, Jensen MO, Hansen FY, et al. (2007) Reparameterization of all-atom dipalmitoylphosphatidylcholine lipid parameters enables simulation of fluid bilayers at zero tension. Biophys J 92: 4157–4167.    
  • 41. Venturoli M, Smit B, Sperotto MM (2005) Simulation studies of protein-induced bilayer deformations, and lipid-induced protein tilting, on a mesoscopic model for lipid bilayers with embedded proteins. Biophys J 88: 1778–1798.    
  • 42. Chung LA, Lear JD, Degrado WF (1992) Fluorescence studies of the secondary structure and orientation of a model ion channel peptide in phospholipid vesicles. Biochemistry 31: 6608–6616.    
  • 43. Choma C, Gratkowski H, Lear JD, et al. (2000) Asparagine-mediated self-association of a model transmembrane helix. Nat Struct Mol Biol 7: 161–166.    
  • 44. Douliez JP, Leonard A, Dufourc EJ (1995) Restatement of order parameters in biomembranes: Calculation of C-C bond order parameters from C-D quadrupolar splittings. Biophys J 68: 1727–1739.    
  • 45. Douliez JP, Ferrarini A, Dufourc EJ (1998) On the relationship between C-C and C-D order parameters and its use for studying the conformation of lipid acyl chains in biomembranes. J Chem Phys 109: 2513–2518.    
  • 46. Seelig J, Niederberger W (1974) Two pictures of a lipid bilayer. A comparison between deuterium label and spin-label experiments. Biochemistry 13: 1585–1588.
  • 47. Seelig J, Waespesarcevic N (1978) Molecular order in cis and trans unsaturated phospholipid bilayers. Biochemistry 17: 3310–3315.    
  • 48. Smart OS, Breed J, Smith GR, et al. (1997) A novel method for structure-based prediction of ion channel conductance properties. Biophys J 72: 1109–1126.    
  • 49. Smart OS, Neduvelil JG, Wang X, et al. (1996) HOLE: A program for the analysis of the pore dimensions of ion channel structural models. J Mol Graphics 14: 354–360.    
  • 50. Jorgensen WL, Chandrasekhar J, Madura JD, et al. (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79: 926–935.    
  • 51. Zhong Q, Jiang Q, Moore PB, et al. (1998) Molecular dynamics simulation of a synthetic ion channel. Biophys J 74: 3–10.    
  • 52. Larsen RJ, Marx ML (2017) An Introduction to Mathematical Statistics and Its Applications, Pearson, 742.
  • 53. Heijmans RDH, Pollock DSG, Satorra A (2000) Innovations in Multivariate Statistical Analysis, Springer US, 298.
  • 54. Canal L (2005) A normal approximation for the chi-square distribution. Comput Stat Data An 48: 803–808.    


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