Abstract
The rate at which phospholipids equilibrate between different membranes and between the non-polar environments in biological fluids is of high importance in the understanding of biomembrane diversity, as well as in the development of liposomes for drug delivery. In this work, we characterize the rate of insertion into and desorption from POPC bilayers for a homologous series of amphiphiles with the fluorescent NBD group attached to phosphoethanolamines of different acyl chain lengths, NBD-diC n -PE with n = 6, 8, 10, and 12. The rate of translocation between bilayer leaflets was also characterized, providing all the relevant parameters for their interaction with lipid bilayers. The results are complemented with data for NBD-diC14-PE obtained from literature (Abreu et al. Biophys J 87:353–365, 2004; Moreno et al. Biophys J 91:873-881, 2006). The rate of translocation between the POPC leaflets is not dependent on the length of the acyl chains, while this affects strongly the rate of desorption from the bilayer. Insertion in the POPC bilayer is not diffusion controlled showing a significant dependence on the acyl chain length and on temperature. The results obtained are compared with those previously reported for NBD-LysoC14-PE (Sampaio et al. Biophys J 88:4064–4071, 2005), and with the homologous series of single chain amphiphiles NBD-C n (Cardoso et al. J Phys Chem B 114:16337–16346, 2010; J Phys Chem B 115:10098–10108, 2011). This allows the establishment of important relations between the rate constants for interaction with the lipid bilayers and the structural properties of the amphiphiles, namely the total surface and the cross-section of their non-polar region.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abreu MSC, Moreno MJ, Vaz WLC (2004) Kinetics and thermodynamics of association of a phospholipid derivative with lipid bilayers in liquid-disordered and liquid-ordered. Phases Biophys J 87:353–365. https://doi.org/10.1529/biophysj.104.040576
Amaro M, Filipe HAL, Ramalho JPP, Hof M, Loura LMS (2016) Fluorescence of nitrobenzoxadiazole (NBD)-labeled lipids in model membranes is connected not to lipid mobility but to probe location. Phys Chem Chem Phys 18:7042–7054. https://doi.org/10.1039/c5cp05238f
Bozzuto G, Molinari A (2015) Liposomes as nanomedical devices. Int J Nanomed 10:975–999. https://doi.org/10.2147/ijn.s68861
Cardoso RMS, Filipe HAL, Gomes F, Moreira ND, Vaz WLC, Moreno MJ (2010) Chain length effect on the binding of amphiphiles to serum albumin and to POPC bilayers. J Phys Chem B 114:16337–16346. https://doi.org/10.1021/jp105163k
Cardoso RMS, Martins PAT, Gomes F, Doktorovova S, Vaz WLC, Moreno MJ (2011) Chain-length dependence of insertion, desorption, and translocation of a homologous series of 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled aliphatic amines in membranes. J Phys Chem B 115:10098–10108. https://doi.org/10.1021/jp203429s
Colleau M, Herve P, Fellmann P, Devaux PF (1991) Transmembrane diffusion of fluorescent phospholipids in human erythrocytes. Chem Phys Lipids 57:29–37
Cronan JE (2003) Bacterial membrane lipids: where do we stand? Annu Rev Microbiol 57:203–224. https://doi.org/10.1146/annurev.micro.57.030502.090851
Cupp D, Kampf JP, Kleinfeld AM (2004) Fatty acid-albumin complexes and the determination of the transport of long chain free fatty acids across membranes. Biochemistry 43:4473–4481. https://doi.org/10.1021/bi0363351
Devaux PF (1992) Protein Involvement in transmembrane lipid asymmetry. Annu Rev Biophys Biomol Struct 21:417–439. https://doi.org/10.1146/annurev.biophys.21.1.417
Estronca LMBB., Filipe HAL, Salvador A, Moreno MJ, Vaz WLC (2014) Homeostasis of free cholesterol in the blood—a preliminary evaluation and modeling of its passive transport. J Lipid Res 55:1033–1043. https://doi.org/10.1194/jlr.M043067
Estronca LMBB., Moreno MJ, Laranjinha JAN, Almeida LM, Vaz WLC (2005) Kinetics and thermodynamics of lipid amphiphile exchange between lipoproteins and albumin in serum. Biophys J 88:557–565. https://doi.org/10.1529/biophysj.104.047050
Filipe HAL, Moreno MJ, Loura LMS (2011) Interaction of 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled fatty amines with 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine bilayers: a molecular dynamics study. J Phys Chem B 115:10109–10119. https://doi.org/10.1021/jp203532c
Filipe HAL, Salvador A, Silvestre JM, Vaz WLC, Moreno MJ (2014) Beyond overton’s rule: quantitative modeling of passive permeation through Tight Cell Monolayers. Mol Pharm 11:3696–3706. https://doi.org/10.1021/mp500437e
Filipe HAL, Bowman D, Palmeira T, Cardoso RMS, Loura LMS, Moreno MJ (2015a) Interaction of NBD-labelled fatty amines with liquid-ordered membranes: a combined molecular dynamics simulation and fluorescence spectroscopy study. Phys Chem Chem Phys 17:27534–27547. https://doi.org/10.1039/C5CP04191K
Filipe HAL, Santos LS, Ramalho JPP, Moreno MJ, Loura LMS (2015b) Behaviour of NBD-head group labelled phosphatidylethanolamines in POPC bilayers: a molecular dynamics study. Phys Chem Chem Phys 17:20066–20079. https://doi.org/10.1039/c5cp01596k
Gerl MJ et al (2012) Quantitative analysis of the lipidomes of the influenza virus envelope and MDCK cell apical membrane. J Cell Biol 196:213–221. https://doi.org/10.1083/jcb.201108175
Greenwood AI, Tristram-Nagle S, Nagle JF (2006) Partial molecular volumes of lipids and cholesterol. Chem Phys Lipids 143:1–10
Ho JK, Duclos RI, Hamilton JA (2002) Interactions of acyl carnitines with model membranes: a C-13-NMR study. J Lipid Res 43:1429–1439. https://doi.org/10.1194/jlr.M200137-JLR200
Homan R, Pownall HJ (1988) Transbilayer diffusion of phospholipids—dependence on headgroup structure and acyl chain-length. Biochim Biophys Acta 938:155–166
Huster D, Muller P, Arnold K, Herrmann A (2001) Dynamics of membrane penetration of the fluorescent 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) group attached to an acyl chain of phosphatidylcholine. Biophys J 80:822–831
Huster D, Muller P, Arnold K, Herrmann A (2003) Dynamics of lipid chain attached fluorophore 7-nitrobenz-2-oxa-1,3-diazol-4-yI (NBD) in negatively charged membranes determined by NMR spectroscopy. Eur Biophys J 32:47–54
Kleinfeld AM, Chu P, Romero C (1997) Transport of long-chain native fatty acids across lipid bilayer membranes indicates that transbilayer flip-flop is. rate limiting. Biochemistry 36:14146–14158
Kohli AG, Kierstead PH, Venditto VJ, Walsh CL, Szoka FC (2014) Designer lipids for drug delivery: from heads to tails. J Controlled Release 190:274–287. https://doi.org/10.1016/j.jconrel.2014.04.047
Konig B, Dietrich U, Klose G (1997) Hydration and structural properties of mixed lipid/surfactant. Model Membranes Langmuir 13:525–532
Kraft JC, Freeling JP, Wang ZY, Ho RJY (2014) Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J Pharm Sci 103:29–52. https://doi.org/10.1002/jps.23773
Lantzsch G, Binder H, Heerklotz H, Wendling M, Klose G (1996) Surface areas and packing constraints in POPC/C(12)EO(n) membranes. A time-resolved fluorescence study. Biophys Chem 58:289–302
Loura LMS, Fernandes F, Fernandes AC, Ramalho JPP (2008) Effects of fluorescent probe NBD-PC on the structure, dynamics and phase transition of DPPC. A molecular dynamics and differential scanning calorimetry study. Biochim Biophys Acta-Biomembr 1778:491–501
Loura LMS, Ramalho JPP (2007) Location and dynamics of acyl chain NBD-labeled phosphatidylcholine (NBD-PC) in DPPC bilayers. A molecular dynamics and time-resolved fluorescence anisotropy study Biochim. Biophys Acta-Biomembr 1768:467–478
Martins PA, Gomes F, Vaz WLC, Moreno MJ (2008) Binding of phospholipids to á-lactoglobulin and their transfer to lipid bilayers. Biochim Biophys Acta 1778:1308–1315. https://doi.org/10.1016/j.bbamem.2008.02.011
Martins PAT, Moreno MJ (2016) Kinetics of the interaction of amphiphiles with lipid bilayers using ITC. In: Bastos M (ed) Biocalorimetry: foundations and contemporary approaches. Taylor & Francis, Routledge, pp 187–201
Martins PT, Velazquez-Campoy A, Vaz WLC, Cardoso RMS, Valerio J, Moreno MJ (2012) Kinetics and thermodynamics of chlorpromazine interaction with lipid bilayers: effect of charge and cholesterol. J Am Chem Soc 134:4184–4195. https://doi.org/10.1021/ja209917q
Massey JB, Bick DH, Pownall HJ (1997) Spontaneous transfer of monoacyl amphiphiles between lipid and protein surfaces. Biophys J 72:1732–1743
Massey JB, Gotto AM, Pownall HJ (1982) Kinetics and mechanism of the spontaneous transfer of fluorescent phospholipids between apolipoprotein-phospholipid recombinants—effect of the polar headgroup. J Biol Chem 257:5444–5448
Moreno MJ, Estronca LMBB., Vaz WLC (2006) Translocation of phospholipids and dithionite permeability in liquid-ordered and liquid-disordered membranes. Biophys J 91:873–881. https://doi.org/10.1529/biophysj.106.082115
Nichols JW (1985) Thermodynamics and kinetics of phospholipid. Monomer Vesicle Interaction. Biochemistry 24:6390–6398
Nichols JW, Pagano RE (1981) Kinetics of soluble lipid monomer diffusion. Between Vesicles Biochem 20:2783–2789
Pattni BS, Chupin VV, Torchilin VP (2015) New developments in liposomal drug. Deliv Chem Rev 115:10938–10966. https://doi.org/10.1021/acs.chemrev.5b00046
Pokorny A, Almeida PFF, Melo ECC, Vaz WLC (2000) Kinetics of amphiphile association with two-phase lipid bilayer vesicles. Biophys J 78:267–280
Pokorny A, Almeida PFF, Vaz WLC (2001) Association of a fluorescent amphiphile with lipid bilayer vesicles in regions of solid-liquid-disordered phase coexistence. Biophys J 80:1384–1394
Pool CT, Thompson TE (1998) Chain length and temperature dependence of the reversible association of model acylated proteins with Lipid Bilayers. Biochemistry 37:10246–10255
Pownall HJ, Bick DLM, Massey JB (1991) Spontaneous phospholipid transfer—development of a quantitative model. Biochemistry 30:5696–5700
Sampaio JL, Moreno MJ, Vaz WLC (2005) Kinetics and thermodynamics of association of a fluorescent lysophospholipid derivative with lipid bilayers in liquid-ordered and liquid-disordered Phases. Biophys J 88:4064–4071. https://doi.org/10.1529/biophysj.104.054007
Santos A, Rodrigues AM, Sobral A, Monsanto PV, Vaz WLC, Moreno MJ (2009) Early events in photodynamic therapy: chemical and physical changes in a POPC: cholesterol bilayer due to hematoporphyrin IX-mediated. photosensitization. Photochem Photobiol 85:1409–1417. https://doi.org/10.1111/j.1751-1097.2009.00606.x
Sapay N, Bennett WFD, Tieleman DP (2009) Thermodynamics of flip-flop and desorption for a systematic series of phosphatidylcholine lipids. Soft Matter 5:3295–3302. https://doi.org/10.1039/b902376c
Silvius JR, Leventis R (1993) Spontaneous interbilayer transfer of phospholipids—dependence on acyl-chain. Compos Biochem 32:13318–13326
Simard JR, Pillai BK, Hamilton JA (2008) Fatty acid flip-flop in a model membrane is faster than desorption into the aqueous phase. Biochemistry 47:9081–9089. https://doi.org/10.1021/bi800697q
Smaby JM, Momsen MM, Brockman HL, Brown RE (1997) Phosphatidylcholine acyl unsaturation modulates the decrease in interfacial elasticity induced by cholesterol. Biophys J 73:1492–1505
Thomas RM, Baici A, Werder M, Schulthess G, Hauser H (2002) Kinetics and mechanism of long-chain fatty acid transport into phosphatidylcholine vesicles from various donor systems. Biochemistry 41:1591–1601. https://doi.org/10.1021/bi011555p
Tieleman DP, Marrink SJ (2006) Lipids out of equilibrium: energetics of desorption and pore mediated flip-flop. J Am Chem Soc 128:12462–12467
van Meer G (2011) Dynamic transbilayer lipid asymmetry. Cold Spring Harb Perspect Biol 3:a004671. https://doi.org/10.1101/cshperspect.a004671
van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124. https://doi.org/10.1038/nrm2330
Wimley WC, Thompson TE (1990) Exchange and flip-flop of dimyristoylphosphatidylcholine in liquid-crystalline, gel, and 2-component. 2-phase large unilamellar vesicles. Biochemistry 29:1296–1303
Wimley WC, Thompson TE (1991) Transbilayer and Interbilayer phospholipid exchange in dimyristoylphosphatidylcholine dimyristoylphosphatidylethanolamine large unilamellar vesicles. Biochemistry 30:1702–1709
Zhang FL, Kamp F, Hamilton JA (1996) Dissociation of long and very long chain fatty acids from phospholipid bilayers. Biochemistry 35:16055–16060. https://doi.org/10.1021/bi961685b
Acknowledgements
This work was partially supported by the Portuguese “Fundação para a Ciência e a Tecnologia” (FCT) through Projects 007630 UID/QUI/00313/2013 and PT2020_PTDC_DTP-FTO_2784_2014, co-funded by COMPETE2020-UE.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Filipe M Coreta-Gomes, Winchil L. C. Vaz, Maria João Moreno declare that they have no conflict of interest.
Research Involving with Human and Animal Rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Coreta-Gomes, F.M., Vaz, W.L.C. & Moreno, M.J. Effect of Acyl Chain Length on the Rate of Phospholipid Flip-Flop and Intermembrane Transfer. J Membrane Biol 251, 431–442 (2018). https://doi.org/10.1007/s00232-017-0009-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-017-0009-4