Biophysical Reviews

, Volume 10, Issue 5, pp 1371–1376 | Cite as

The effect of H3O+ on the membrane morphology and hydrogen bonding of a phospholipid bilayer

  • Evelyne Deplazes
  • David Poger
  • Bruce Cornell
  • Charles G. CranfieldEmail author


At the 2017 meeting of the Australian Society for Biophysics, we presented the combined results from two recent studies showing how hydronium ions (H3O+) modulate the structure and ion permeability of phospholipid bilayers. In the first study, the impact of H3O+ on lipid packing had been identified using tethered bilayer lipid membranes in conjunction with electrical impedance spectroscopy and neutron reflectometry. The increased presence of H3O+ (i.e. lower pH) led to a significant reduction in membrane conductivity and increased membrane thickness. A first-order explanation for the effect was assigned to alterations in the steric packing of the membrane lipids. Changes in packing were described by a critical packing parameter (CPP) related to the interfacial area and volume and shape of the membrane lipids. We proposed that increasing the concentraton of H3O+ resulted in stronger hydrogen bonding between the phosphate oxygens at the water–lipid interface leading to a reduced area per lipid and slightly increased membrane thickness. At the meeting, a molecular model for these pH effects based on the result of our second study was presented. Multiple μs-long, unrestrained molecular dynamic (MD) simulations of a phosphatidylcholine lipid bilayer were carried out and showed a concentration dependent reduction in the area per lipid and an increase in bilayer thickness, in agreement with experimental data. Further, H3O+ preferentially accumulated at the water–lipid interface, suggesting the localised pH at the membrane surface is much lower than the bulk bathing solution. Another significant finding was that the hydrogen bonds formed by H3O+ ions with lipid headgroup oxygens are, on average, shorter in length and longer-lived than the ones formed in bulk water. In addition, the H3O+ ions resided for longer periods in association with the carbonyl oxygens than with either phosphate oxygen in lipids. In summary, the MD simulations support a model where the hydrogen bonding capacity of H3O+ for carbonyl and phosphate oxygens is the origin of the pH-induced changes in lipid packing in phospholipid membranes. These molecular-level studies are an important step towards a better understanding of the effect of pH on biological membranes.


H3O+ Phospholipid bilayers Hydrogen bonding Critical packing parameter Molecular dynamics simulations 


Compliance with ethical standards

Conflict of interest

Evelyne Deplazes declares that she has no conflict of interest. David Poger declares that he has no conflict of interest. Bruce Cornell declares that he has no conflict of interest. Charles G Cranfield declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Aroti A, Leontidis E, Dubois M, Zemb T (2007) Effects of monovalent anions of the hofmeister series on DPPC lipid bilayers part I: swelling and in-plane equations of state. Biophys J 93:1580–1590CrossRefGoogle Scholar
  2. Basu R, De S, Ghosh D, Nandy P (2001) Nonlinear conduction in bilayer lipid membranes – effect of temperature. Physica A: Statistical Mechanics and its Applications 292:146–152CrossRefGoogle Scholar
  3. Berkowitz ML, Vácha R (2012) Aqueous solutions at the interface with phospholipid bilayers. Acc Chem Res 45:74–82CrossRefGoogle Scholar
  4. Blicher A, Wodzinska K, Fidorra M, Winterhalter M, Heimburg T (2009) The temperature dependence of lipid membrane permeability, its quantized nature, and the influence of anesthetics. Biophys J 96:4581–4591CrossRefGoogle Scholar
  5. Bonthuis DJ, Mamatkulov SI, Netz RR (2016) Optimization of classical nonpolarizable force fields for OH and H3O+. J Chem Phys 144:104503CrossRefGoogle Scholar
  6. Brändén M, Sandén T, Brzezinski P, Widengren J (2006) Localized proton microcircuits at the biological membrane–water interface. Proc Natl Acad Sci U S A 103:19766–19770CrossRefGoogle Scholar
  7. Carreira AC, De Almeida RFM, Silva LC (2017) Development of lysosome-mimicking vesicles to study the effect of abnormal accumulation of sphingosine on membrane properties. Sci Rep 7:3949CrossRefGoogle Scholar
  8. Chen R, Poger D, Mark AE (2011) Effect of high pressure on fully hydrated DPPC and POPC bilayers. J Phys Chem B 115:1038–1044CrossRefGoogle Scholar
  9. Chialvo AA, Cummings PT, Simonson JM (2000) H3O+/Cl ion-pair formation in high-temperature aqueous solutions. J Chem Phys 113:8093–8100CrossRefGoogle Scholar
  10. Cranfield CG, Berry T, Holt SA, Hossain KR, Le Brun AP, Carne S, Al Khamici H, Coster H, Valenzuela SM, Cornell B (2016) Evidence of the key role of H3O+ in phospholipid membrane morphology. Langmuir 32:10725–10734CrossRefGoogle Scholar
  11. Cranfield CG, Henriques ST, Martinac B, Duckworth PA, Craik DJ, Cornell B (2017) Kalata B1 and Kalata B2 have a surfactant-like activity in phosphatidylethanolomine containing lipid membranes. LangmuirGoogle Scholar
  12. Dang LX (2003) Solvation of the hydronium ion at the water liquid/vapor interface. J Chem Phys 119:6351–6353CrossRefGoogle Scholar
  13. De Rosa M, Gambacorta A, Nicolaus B, Grant WD (1983) A C25,C25 diether core lipid from archaebacterial haloalkaliphiles. Microbiology 129:2333–2337CrossRefGoogle Scholar
  14. Deplazes E, Poger D, Cornell B, Cranfield CG (2018) The effect of hydronium ions on the structure of phospholipid membranes. Phys Chem Chem Phys 20:357–366CrossRefGoogle Scholar
  15. Disalvo EA (2015) Membrane hydration: a hint to a new model for biomembranes (Chapter 1). In membrane hydration – the role of water in the structure and function of biological membranesGoogle Scholar
  16. Gennis RB (2016) Proton dynamics at the membrane surface. Biophys J 110:1909–1911CrossRefGoogle Scholar
  17. Gertner BJ, Hynes JT (1998) Model molecular dynamics simulation of hydrochloric acid ionization at the surface of stratospheric ice. Faraday Discuss 110:301–322CrossRefGoogle Scholar
  18. Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56:1194–1198PubMedGoogle Scholar
  19. Gopta OA, Cherepanov DA, Junge W, Mulkidjanian AY (1999) Proton transfer from the bulk to the bound ubiquinone QB of the reaction center in chromatophores of Rhodobacter sphaeroides: retarded conveyance by neutral water. Proc Natl Acad Sci U S A 96:13159–13164CrossRefGoogle Scholar
  20. Heberle J, Riesle J, Thiedemann G, Oesterhelt D, Dencher NA (1994) Proton migration along the membrane surface and retarded surface to bulk transfer. Nature 370:379–382CrossRefGoogle Scholar
  21. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447CrossRefGoogle Scholar
  22. Huang Y, Mcnamara JO (2004) Ischemic stroke. Cell 118:665–666CrossRefGoogle Scholar
  23. Israelachvili JN, Mitchell DJ, Ninham BW (1976) Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. J Chem Soc Faraday Trans 2(72):1525–1568CrossRefGoogle Scholar
  24. Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, Baba Y (2013) Acidic extracellular microenvironment and cancer. Cancer Cell Int 13:89CrossRefGoogle Scholar
  25. Kellum JA, Song M, Li J (2004) Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Crit Care 8:331CrossRefGoogle Scholar
  26. Khaleque HN, Ramsay JP, Murphy RJ, Kaksonen AH, Boxall NJ, Watkin EL (2017) Draft genome sequence of the acidophilic, halotolerant, and iron/sulfur-oxidizing Acidihalobacter prosperus DSM 14174 (strain V6). Genome Announc 5:e01469–e01416PubMedPubMedCentralGoogle Scholar
  27. Krämer SD, Braun A, Jakits-Deiser C, Wunderli-Allenspach H (1998) Towards the predictability of drug-lipid membrane interactions: the pH-dependent affinity of propranolol to phosphatidylinositol containing liposomes. Pharm Res 15:739–744CrossRefGoogle Scholar
  28. Krulwich TA, Sachs G, Padan E (2011) Molecular aspects of bacterial pH sensing and homeostasis. Nat Rev Microbiol 9:330–343CrossRefGoogle Scholar
  29. Kusaka I, Wang ZG, Seinfeld JH (1998) Binary nucleation of sulfuric acid-water: Monte Carlo simulation. J Chem Phys 108:6829–6848CrossRefGoogle Scholar
  30. Lagadic-Gossman D, Huc L, Lecureur V (2004) Alterations of intralellular pH homeostastasis in apoptosis: origins and roles. Cell Death Differ 11:953–961CrossRefGoogle Scholar
  31. Mashaghi A, Partovi-Azar P, Jadidi T, Anvari M, Jand SP, Nafari N, Tabar MRR, Maass P, Bakker HJ, Bonn M (2013) Enhanced autoionization of water at phospholipid interfaces. J Phys Chem C 117:510–514CrossRefGoogle Scholar
  32. Milhaud J (2003) New insights into water-phospholipid model membrane interactions. Biochim Biophys Acta 1663:19–5.1CrossRefGoogle Scholar
  33. Pearson RH, Pascher I (1979) The molecular structure of lecithin dihydrate. Nature 281:499–501CrossRefGoogle Scholar
  34. Petrache HI, Zemb T, Belloni L, Parsegian VA (2006) Salt screening and specific ion adsorption determine neutral-lipid membrane interactions. Proc Natl Acad Sci U S A 103:7982–7987CrossRefGoogle Scholar
  35. Poger D, Mark AE (2009) On the validation of molecular dynamics simulations of saturated and cis-monounsaturated phosphatidylcholine lipid bilayers: a comparison with experiment. J Chem Theory Comput 6:325–336CrossRefGoogle Scholar
  36. Poger D, Mark AE (2012) Lipid bilayers: the effect of force field on ordering and dynamics. J Chem Theory Comput 8:4807–4817CrossRefGoogle Scholar
  37. Poger D, van Gunsteren WF, Mark AE (2010) A new force field for simulating phosphatidylcholine bilayers. J Comput Chem 31:1117–1125CrossRefGoogle Scholar
  38. Redfern DA, Gericke A (2005) pH-dependent domain formation in phosphatidylinositol polyphosphate/phosphatidylcholine mixed vesicles. J Lipid Res 46:504–515CrossRefGoogle Scholar
  39. Schaper K-J, Zhang H, Raevsky OA (2001) pH-dependent partitioning of acidic and basic drugs into liposomes—a quantitative structure-activity relationship analysis. Quant Struct-Act Relat 20:46–54CrossRefGoogle Scholar
  40. Schmid N, Eichenberger AP, Choutko A, Riniker S, Winger M, Mark AE, van Gunsteren WF (2011) Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur Biophys J 40:843–856CrossRefGoogle Scholar
  41. Slevin CJ, Unwin PR (2000) Lateral proton diffusion rates along stearic acid monolayers. J Am Chem Soc 122:2597–2602CrossRefGoogle Scholar
  42. Smondyrev AM, Voth GA (2002) Molecular dynamics simulation of proton transport near the surface of a phospholipid membrane. Biophys J 82:1460–1468CrossRefGoogle Scholar
  43. Song J, Franck J, Pincus P, Kim MW, Han S (2014) Specific ions modulate diffusion dynamics of hydration water on lipid membrane surfaces. J Am Chem Soc 136:2642–2649CrossRefGoogle Scholar
  44. Urata S, Irisawa J, Takada A, Shinoda W, Tsuzuki S, Mikami M (2005) Molecular dynamics simulation of swollen membrane of perfluorinated ionomer. J Phys Chem B 109:4269–4278CrossRefGoogle Scholar
  45. Vácha R, Buch V, Milet A, Devlin JP, Jungwirth P (2007) Autoionization at the surface of neat water: is the top layer pH neutral, basic, or acidic? Phys Chem Chem Phys 9:4736–4747CrossRefGoogle Scholar
  46. Veatch SL, Keller SL (2005) Seeing spots: complex phase behavior in simple membranes. Biochim Biophys Acta 1746:172–185CrossRefGoogle Scholar
  47. Winter R (2001) Effects of hydrostatic pressure on lipid and surfactant phases. Curr Opin Colloid Interface Sci 6:303–312CrossRefGoogle Scholar
  48. Wolf MG, Grubmüller H, Groenhof G (2014) Anomalous surface diffusion of protons on lipid membranes. Biophys J 107:76–87CrossRefGoogle Scholar
  49. Yamashita T, Voth GA (2010) Properties of hydrated excess protons near phospholipid bilayers. J Phys Chem B 114:592–603CrossRefGoogle Scholar
  50. Zhang C, Knyazev DG, Vereshaga YA, Ippoliti E, Nguyen TH, Carloni P, Pohl P (2011) Water at hydrophobic interfaces delays proton surface-to-bulk transfer and provides a pathway for lateral proton diffusion. Proc Natl Acad Sci U S A 109:9744–9749CrossRefGoogle Scholar
  51. Ziemann AE, Schnizler MK, Albert GW, Severson MA, Howard MA III, Welsh MJ, Wemmie JA (2008) Seizure termination by acidosis depends on ASIC1a. Nat Neurosci 11:816–822CrossRefGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute and Curtin Institute for ComputationCurtin UniversityPerthAustralia
  2. 2.School of Chemistry and Molecular BiosciencesThe University of QueenslandBrisbaneAustralia
  3. 3.SDx Tethered Membranes Pty. Ltd.RosevilleAustralia
  4. 4.School of Life SciencesUniversity of Technology SydneyUltimoAustralia

Personalised recommendations