Czaplewski, C.

Danne, R.

Duburs, G.

Liepina, I.

Ose, V.

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John von Neumann Institute for Computing1.4-DHP-Lipid Forms a Tubular MicellaeI. Liepina, C. Czaplewski, V. Ose, R. Danne, G. Duburspublished inFrom Computational Biophysics to Systems Biology (CBSB08),Proceedings of the NIC Workshop 2008,Ulrich H. E. Hansmann, Jan H. Meinke, Sandipan Mohanty,Walter Nadler, Olav Zimmermann (Editors),John von Neumann Institute for Computing, Ju¨lich,NIC Series, Vol. 40, ISBN 978-3-9810843-6-8, pp. 305-308, 2008.c© 2008 by John von Neumann Institute for ComputingPermission to make digital or hard copies of portions of this work forpersonal or classroom use is granted provided that the copies are notmade or distributed for profit or commercial advantage and that copiesbear this notice and the full citation on the first page. To copy otherwiserequires prior specific permission by the publisher mentioned above.http://www.fz-juelich.de/nic-series/volume401.4-DHP-Lipid Forms a Tubular MicellaeInta Liepina1,2, Cezary Czaplewski3, Velta Ose4,Reinis Danne1,2, and Gunars Duburs11 Latvian Institute of Organic Synthesis, Riga LV1006, LatviaE-mail: inta@osi.lv gduburs@osi.lv2 Center of Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, FinlandE-mail: reinis.danne@helsinki.fi3 Faculty of Chemistry, University of Gdan´sk, 80-952 Gdan´sk, PolandE-mail: czarek@chemik.chem.univ.gda.pl4 Latvian Biomedical Research and Study Centre, Riga LV1067, LatviaE-mail: velta@biomed.lu.lvThe cationic lipid 1,1.-[3,5-bis(dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridin-2,6-diyl]dimethylene bispyridinium dibromide (1,4-DHP lipid), a gene transfection agent, formed atubular micellae during the molecular dynamics simulation with AMBER 8.0 force field. Resultwas confirmed with the electron microscopy showing extended, worm-like structures.1 IntroductionNon-viral gene delivery based on self-assembling structures is an effective medicaltool. The cationic lipid 1,1.-[3,5-bis(dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridin-2,6-diyl] dimethylene bispyridinium dibromide (1,4-DHP lipid, charge q=+2) (Fig. 1) isa gene transfection agent.1, 2 The electronic structure of 1,4-DHP lipid molecule was in-vestigated by ab initio quantum mechanics, and the supramolecular structure formed by1,4-DHP lipid molecules was investigated by means of molecular dynamics simulation.Figure 1. 1,4-DHP lipid molecule.3052 Methods, Results and Discussion1,4-DHP lipid structure was calculated by Restricted Hartree-Fock (RHF) ab initio quan-tum mechanics, 6-31G* bases set, to obtain the charges for molecular dynamics usingRESP algorithm (electrostatical potential based method using charge restrains for deter-mining atom-centered charges). 72 molecules of 1,4-DHP-lipid were subjected to MD(AMBER 8.0 force field, NTP protocol) from the initial structure of a periodic lipid bilayer-water box, with a small amount of excessive water on the lipid edges to ensure the mobilityof lipid molecules. Temperature was risen gradually from T=10 K by step of 10 degrees till300 K. After 35 ns of MD simulation few lipid molecules turned with their charged headsto the side of the lipid bilayer and after 100 ns a profound tubular micelle structure beganto form. The tubular micelle structure (Fig. 2) becomes more perfect during the course ofsimulation of 300 ns.Figure 2. 1,4-DHP lipid tubomicellae side view and top view.The results of MD simulation were confirmed by electron microscopy, showing theinterwinding tubular structures (Fig. 3).Figure 3. Electron microscopy of the 1,4-DHP lipid.306Conclusion is that one of the gene transfection agent 1,4-DHP lipid structures is atubular micellae, and we could expect that such the micellaes are capable to form a lipoplexfor the DNA transfectionAcknowledgmentsThis work was supported by Stipend of Finland Academy of Sciences for IL, and by Lat-vian Science Council Grant 05.1768. Calculations were performed on computers of theGdansk Academic Computer Centre TASK.References1. Z. Hyvonen, A. Plotniece, I. Reine, B. Chekavichus, G. Duburs, A. Urtti, Novelcationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery, Biochim.Biophys. Acta 1509, 451-466, 2000.2. Z. Hyvonen, S. Ronkko, M.-R. Toppinen, I. Jaaskelainen, A. Plotniece,A .Urtti,Dioleoyl phosphatidylethanolamine and PEG-lipid conjugates modify DNAdelivery mediated by 1,4-dihydropyridine amphiphiles, J. Controlled Release 99, 177-190, 2004.307

1.4-DHP-Lipid Forms a Tubular Micellae

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1.4-DHP-Lipid Forms a Tubular Micellae

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