Invited lecture at the Int.

Summer School on Molecular Modelling and Drug Design,

Yeditepe University, Istanbul, Turkey, September 10-14, 2008.

Yedetipe University, Istanbul, Turkey

Kazan State University (since 1804), Kazan Zavoisky Phisical and Technical Institute,
Kazan, RF

Nucleic acid - lipidous medicines and nucleic acid -

lipid/membrane interactions and complexes:
importance, structure, stability, and modeling.
Pharmacolipidomics.
Renad Zhdanov1, Turkey / Russia, and Rim Daminov2, Russia
1 Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey
2
Zavoisky Physical & Technical Institute, Russian Academy of Sciences, Kazan, RF
Kazan State University (since 1804)

City of Kazan – a capital of Republic of Tatarstan, Russian Federation

Kazan Chemical School (since mid. XIX cent.) - origin of organic chemistry in Russia

Discovery of many organic reactions and compounds

Nikolay ZININ (reduction of nitrobenzen to anilin),

Alexander BUTLEROV (theory of the structure of
chemical compounds, 1869),
Vladimir MARKOVNIKOW (Markovnikow rules),
Alexander ZAITSEV (Zaitsev reaction),
Alexander and Boris ARBUZOV (Arbuzov reaction)

Creation of non-Euclid geometry

by Nikolai Lobachevsky (rector for 20 years)

Discovery of magnetic resonance phenomenon, ESR, 1944

by Eugenyi ZAVOISKY (Lenin Prize winer)

Motivation of the talk: to present to computitional scientists new exciting
area of DNA-bound lipids which has great potential
for drug design and which is a part of pharmacolipidomics.

They are “targets looking for drugs” – M. Botta

Contents:

Main biomacromolecules and their interactions

Lipids in cell and lipidomics.

Hydrophobic and lipidous medicines; minor groove binders: antibiotics, peptides

Role lipids in nucleus: chromatin stabilization, signal transduction and regulation of gene

expression

There are lipids and phospholipids tightly bound to

genomic DNA: lipid code of DNA or DNA-bound lipoproteins?

Binding lipids to DNA: DNA-lipid recognition. How can lipids bind to DNA?

Experimental data on lipid binding to DNA

Computer experiments on binding fatty acids and cholesterol to DNA

DNA-phospholipid recognition

“Cardiolipin mistery”

Modeling DNA-membrane complexes

DNA-cationic lipid complexes – lipoplexes – for gene therapy

 Main classes of biomacromolecules:
nucleic acids

proteins

carbohydrates

lipids
The study of:

lipid – protein interactions and complexes – 1960-1980

DNA – protein interactions and complexes – 1980-2000

nucleic acids – lipid interactions and complexes – 1990-2010

nucleic acids – carbohydrates interactions and complexes – very few

data
 System biology topics:

Genome
Proteome
Transcriptome
Lipidome
Glycome
Metabolomics
Regulomics
Signalomics
Fluxomics
Interactomics
Pathogenomics
Pathophysiolomics
Nutrigenomics
Pharmacolipidomics
 Properties and Function of Lipids

• amphiphilic with hydrophobic • membrane formation

and hydrophilic properties

• energy source
• strong tendency to self-

organization • regulatory function

• protein-complex formation
• signaling function
• linking up with carbohydrates

• medicines
 Lipid content of cell
ACYLGLYCEROLES HORANOIDS
BILE ACIDS (CHOLANOIDS) ISOPRENOIDS
LIPID PEROXIDES OXYLIPINS
DERIVED LIPIDS LIPOAMINO ACIDS
FATTY ACID LIPONUCLEOTIDES
LONG CHAIN ALCOHOL LIPOPOLYSACCHARIDES
ALDEHYDE LIPOPROTEINS
CERAMIDES MYCOLIC ACIDS

EICOSANOIDS PHOSPHOLIPIDS
ETHER TYPE LIPIDS GLYCEROPHOSPHOLIPID
FAT SOLUBLE VITAMINES PAF
CAROTENOID LYSO FORMS
COENZYME Q SPHINGOPHOSPHOLIPID
VITAMIN A, D, E, K STEROIDS
GLYCOLIPIDS WAXES
glycoSPHINGOLIPIDS
glycoGLYCEROLIPIDS LIPID BANK FOR WEB DATABASE, JAPAN
etc http://lipidbank.jp/index.shtml
 Topics and problems in lipidomics:
 Physiological reason for lipid diversity.
 Why are there more than 1000 types of lipid molecules
when it is needed for membrane structure organisation
only one, e.g. phosphatidyl choline?
 How can we do cancer diagnostics and treatment using
sphyngomyelines profile?
 How is it possible to study function of genes and
coresponding proteins using the level of cell lipid
metabolites?
 Physiological functions of signal transduction via lipid
messengers.
 Can peculiarities of nutrition and environment influence
fatty acid and lipid profile of DNA-bound lipids?
 Function of lipid molecules in chromatin.
Lipids as Medicine & Lipids in Medicine
 Lipid vitamins and bioantioxidants: vitamin A, a-tocopherol
 Hydrophobic antibiotics: distamycin A, anthramycin, CC-1065
 Hydrophobic peptides
 Flavonoids and polyflavonoids: resveretrol - “medicine against time”,
only drug for long living, fas group genes effector
 W3 polyunsaturated acids: MaxEPA, Omacor, Proepa, Sea-omega (30, 70), Omega-500,
fatty acids w6/w3 ratio is: in sun flower oil – 220, in olive oil – 6, and,
according to EC requirements, this ratio for our nutrition should be equal to 3.
eicosapentaenoic – EPA - and docosahexaenoic – DHA – acids have important biological
functions in CNS, and are used in the treatment of psychiatric disorders
Essential and eicosapolyenic fatty acids: linoleic, arachidonic, eicosapentaenic acids
Medicines - minor groove binders
 Diseases of lipid exchange: lipodystrophy, obesity
 Lipid-lowering medicines; lipid-altering medications; lipid-regulating drugs: 3-Hydroxy-
3-methylglutaryl coenzyme A (HMG CoA) Reductase inhibitors; lipid-modifying drugs
 Five groups of anti-lipid drugs: statins, fibrates, anion-exchange resins, nicotinic acids and
fish oils
 Fatty acid synthase as a target for drugs against obesity
Very recent event! Atomic structure of the mammalian “fatty acid factory” determined by
Swiss researchers – Science, 5 September 2008: 321, # 5894, 1315-1322
 Lipid emulsions and liposomes in drug delivery
 Cationic lipids – non-viral gene delivery systems
 Overview of DNA-lipid and DNA-membrane
studies :
 Principles of structural organization and functioning of supra-
molecular DNA/RNA-Me(II) ions-Ph membrane triple systems
as model DNA-membrane contacts;

 Sequence-specific DNA- lipid binding;

 Computer modelling DNA-binding lipids and membranes;
 RNA-lipid interactions and origin of life ;

 New non-viral lipid systems for gene transfer in vitro and gene
delivery in vivo;
 Self assembling non-viral gene delivery systems;

 Lipidomics and BAME analysis of DNA-binding lipids of

prokaryotic cells to study whether they participate in cell
response to general stress;
 Lipidomics and FAME analysis of DNA-binding lipids under
pathology: hyperhomocysteinemia, antiphospholipid syndrom…
 DNA isolation

R. Zhdanov et al (2006) FEMS Microbiol. Lett

 NUCLEIC ACIDS IN CHROMATIN WERE
CONSIDERED AS JUST NUCLEI BUFFER SYSTEM
and „WASTE“ EVEN IN 1930s

~ 1% w/w of nuclear lipids are chromatin-

bound. What are their functions?
NUCLEAR LIPIDS ARE NOT ONLY FORMING
SCAFFOLD, BUT CAN PARTICIPATE IN
REGULATION OF GENE EXPRESSION, chromatin
stabilization and signal transduction
 Phospholipid molecules are involved into
regulation of structural and functional
properties of nuclear matrix.
 Phospholipids are responsible for
hydrophobic interactions between nucleic
acids and matrix fibrilla via (directly or not
directly) association with matrix non-histone
proteins.

Cocco L., Manzoli L., Maraldi N. et al

Basic Appl.Histochemistry 1987, v.31, # 3, 413-419.
 Why and how can lipids interact with DNA?

CONTRA:

Lipids are hydrophobic, and DNA is hydrophilic

Lipids are biomacromolecules

How negatively charged fatty acid or cardiolipin will interact with
negatively charged DNA

How can DNA recognize small oily molecule

PRO:

Lipids are amphiphilic, and DNA has hydrophobic profiles

Lipids are low molecular mass compounds

Hydrophobic, van der Vaals, dispersion interactions are important

Lipid recognition by AT-rich DNA sequences
Oleic acid recognition by DNA R. Zhdanov et al. J. Biomol. Struct. Dyn. 2002, Vol 20, pp. 231-242

CD-SPECTRA OF poly [d(C-G)] DUPLEX FOR DIFFERENT

OLEIC ACID:BASE PAIR RATIO

CD-SPECTRA OF poly [d(C-G)] DUPLEX FOR DIFFERENT
OLEIC ACID:BASE PAIR RATIO

ratio ligand per b.p.

ROLE OF DNA STRUCTURE
 How are lipids bound to DNA?

Hydrophobic profile of DNA grooves (blue)

Biophysical modelling
(CD-and UV-spectroscopy, atomic force microsocpy, biosensors
and DNA microchipd) and computer experiments using
molecular mechanics methods
SENSOBI chemosensors. Complexes of cholesterol (А) and oleic
acid (B) with DNA polynucleotides

А B
 AFM images o poly[d(A-T)]n
а), no oleic acid; b) in the presence of oleic acid
а с) after dialysis; zoom of c)

zoom

в
 Methods used:
Molecular mechanics with:
HyperChem 7.5, MM+
AutoDoc 3.0, AMBER

Free bonding energy

Docking energy for receptor

Outlooks:
Quantum chemistry calculations with ab-initio methods

Modeling CL complexes of “cardiolipin machinery”:

DNA - cardiolipin – DNA

membrane – cardiolipin – cytochrome c

DNA – cardiolipin – cytochrome c

 HyperChem molecular mechanics modeling DNA-oleic acid complexation

Computer models of DNA-oleic acid complex Formation energy of DNA-fatty acids complexes (kcal/mol, vacuo)

[(GC)5-left and (AT)5-right]

70

60

50

40

30
(CG)
20 (AT) 10-
(18:3)
(CG) 10-
10- (18:3)
(AT)
10 (CG) 10- (18:2)
(18:2)
(A) 10- 10-
(18:1) (18:1)
0 (CG)
10-
(AT)
Cholesterol (18:0) (18:1) (18:2) (18:3) 10- (18:0)
(18:0)

R. Zhdanov, P. D'yachkov et al. Rus.Chem.Bull. 2003, 52, 1794

2 (trans), 3 (cis) 4 (trans,trans), 5 (cis,cis) 6 (trans,trans,trans), 7(cis,cis,cis)

Total energies (Etot) and bond energies (Ebond) of DNA

complexes with fatty acids located in either the minor or the
major groove of DNA (Min and Maj, respectively)

Equilibrium geometries of the complexes formed by
oligo(AT)10 with the stearic (a), oleic (b), linoleic (c), and
linolenic (d) acids in the minor grove optimized using the results
of molecular mechanics calculations (the two DNA strands are
shown in gray and white and the fatty acid is shown in black). Fatty acids and the corresponding staggered configurations optimized by ММ+ calcul

Zhdanov R. et al (2003) Rus. Chem. Bul.

AT-specificity of DNA – cholesterol interaction:
DNA microarray and molecular modeling

18

16
AT TAT T
ATAT T A
AT AAT T
14 T TT AT A
T TAAT A
T TT T TT
T T T ATT
AT GATT
12 GT AAT T
TT AAT G
TT T TT G
AT AGT T
А. B.
CT T TT T
CTAT T T
10 ATT T GG
TGAT T C
TT CGTA
AT GTGT
T GAAGG
8 TT T T GC
CGT T T A
AGAGT G
T GCGT A
T GGATG
T TGT GC
Energies of formation of DNA complexes with choles
6 CGACT A
GT GT TG
AGCCT A
CGGATG
terol and its esters for ligand arrangement in the minor (m) or
GTGGT G
T GCAGG
4 T T GCGG
GT CAGG
CGACGA
major (M) grooves
CT GGGT
GGCCGA
2 CGT CGC
GGT CGG
CGACGC
GGGCGA
CGGGT G
0 CGCCGA

1(AT )2(AT )3(AT)4(AT )5(AT)6(AT )

C.

Zhdanov R. et al (2005) Rus. Chem. Bul.

Sequens-specific DNA-lipid/cholesterol interaction: microarray assay
Interaction with oleic acid
CGCCGC CGCCGA CTGGGT AGCCTA CGTTTA CTATTT TTTATT
DNA chip sequences complexed with oleic acid.
GGCGGG CGGGTG CGACGA GTGTTG TTTTGC CTTTTT TTTTTT Normal letter shape corresponds to unchanged
fluorescence intensity (1.0 ± 0.2, normalized
GGCCGC GGGCGA GTCAGG CGACTA TGAAGG ATAGTT TTAATA values). Reduced letter size (grey-italic)
corresponds to diminished fluorescence intensity
GGGGGG CGACGC TTGCGG TTGTGC ATGTGT TTTTTG TTTATA (range 0 to 0.5). Increased letter size corresponds
to increased fluorescence intensity (range 2 to
CGGCGC GGTCGG TGCAGG TGGATG TTCGTA TTAATG ATAATT 17). Most sequences are not influenced by oleic
acid presence.
CGGGGC CGTCGC GTGGTG TGCGTA TGATTC GTAATT ATATTA

GGGCGC GGCCGA CGGATG AGAGTG ATTTGG ATGATT ATTATT

Interaction with cholesterol

CGCCGC CGCCGA CTGGGT AGCCTA CGTTTA CTATTT TTTATT
DNA chip sequences complexed with cholesterol.
GGCGGG CGGGTG CGACGA GTGTTG TTTTGC CTTTTT TTTTTT Most sequences are not influenced by cholesterol.

GGCCGC GGGCGA GTCAGG CGACTA TGAAGG ATAGTT TTAATA

GGGGGG CGACGC TTGCGG TTGTGC ATGTGT TTTTTG TTTATA

CGGCGC GGTCGG TGCAGG TGGATG TTCGTA TTAATG ATAATT

CGGGGC CGTCGC GTGGTG TGCGTA TGATTC GTAATT ATATTA

GGGCGC GGCCGA CGGATG AGAGTG ATTTGG ATGATT ATTATT

Values of bonding and docking energy (кcal/моl) for interaction between DNA oligomers
and C18 fatty acids and cholesterol (Нуperchem 7.5, AutoDock 3.0)

* - Geometry optimized in water cube

(1100 molecules) 35Å x35Å x35Å

** - major groove
Computer modeling DNA-fatty acid complexes
[oleic acid + (GC)5 (lefft) or (AT)5 (right)]
 Formation energy of DNA-fatty acid complexes
(kcal/mol, gas)

70

60

50

40

30
(CG)
20 (AT) 10-
(18:3)
(CG) 10-
10- (18:3)
(AT)
10 (CG) 10- (18:2)
10- (18:2)
(AT)
(18:1)
0 (CG)
10-
10-
(18:1)
(AT)
Cholesterol (18:0) (18:1) (18:2) (18:3) 10- (18:0)
(18:0)

R. Zhdanov, P. Dyachkov, et al. Rus. Chem. Bull. 2003, 52, 1794; 2005, 54, 2138
Values of bonding and docking energy (кcal/моl) for interaction
between DNA oligomers and C18 fatty acids and cholesterol
(Нуperchem 7.5, AutoDock 3.0)
А10·Т10 G10·C10 (АТ)5 (GC)5

Еbond Edocking Еbond Edockim Еbond Edocking Еbond Edocking

g

С 18:0 -8,56 -14,00 -7,53 -12,80 -10,20 -15,70 -8,03 -13,40

18:1 -8,65 -13,80 -7,95 -13,00 -10,40 -15,70 -8,60 -13,60

18:2 -8,66 -13,40 -8,04 -12,70 -9,99 -14,60 9,38** -4,50**

18:3 -9,12 -13,50 -8,17 -12,40 -10,30 -14,80 -8,88 -13,20

Cholester -11,70 -12,60 -12,00 -13,20 -10,70 -11,50 -12,00 -13,30

ol
* Geometry is optimized in water cube (1100 молекул) 35Å x35Å x35Å
* * - majo groove бороздка
Е= - 2757,5 кcal/mol
 Oleate molecule does not bind to DNA major groove: NMR Proof
400 MHz, 300 K

oligoDNA
OligoDNA + oleic acid

OligoDNA + oleic acid

OligoDNA + oleic acid

annealing ethanol DNA denaturation

 Сardiolipin “mystery”
&
Cardiolipin “machinery”
 LIPID CONCEPT in CHROMATIN
ORGANIZATION
DNA-binding CL - PhL of proliferation

• Cardiolipin, CL, has a common structural motive

with DNA
• ~All amount of chromatin CL is bound to DNA
• CL is characteristic for „active“ genome
• CL removes H1 histone from linker DNA
• CL regulates DNA replication, and it is a part of
replisome
• CL promotes B-form-to-A-form transition
• CL is localized at the site of DNA loop-matrix
contact
LIPID CONCEPT in CHROMATIN ORGANIZATION
DNA-bound CL - PhL of proliferation

. R. Zhdanov et al (2001) Cytobios

Кардиолипин и ДНК имеют сходные структурные мотивы
Cardiolipin “mistery”
Cardiolipin bridge between two DNA double helixes

DNA Cardiolipin
 Sequence-specific cardiolipin complexing to DNA, revealed by SensobiTM chemosensor

Formation of DNA liquid crystalline structures in the presence of PEG and cardiolipin
∆А*10-6 о.е.

1- no cardiolipin
2- 3.6*10-5 М
3- 9.4*10-5 М CD spectroscopy 
4- 1.2*10-4 М
[C DNA ]= 2*10-5 М (PEG 340, 0.3 М NaCl, рН 6,8)
5- 1.5*10-4 М
6- 3,1*10-4 М [С cardiolipin] от 3.6*10-5 до 5.9*10-4 M
7- 5.9*10-4 М

nм
Formation of DNA liquid crystalline structures in the
presence of PEG and cardiolipin

5
о.е.

6 1- without cardiolipin
∆А*10-6

7 2- 3.6*10-5 М
3- 9.4*10-5 М
4 4- 1.2*10-4 М
5- 1.5*10-4 М
3 6- 3,1*10-4 М
7- 5.9*10-4 М
2
1
nм
(circular dichroism spectroscopy)
[CDNA ]= 2*10-5 М (PEG 340, 0.3 М NaCl, рН 6,8)
[С cardiolipin] from 3.6*10-5 to 5.9*10-4 M
 Interaction between cardiolipin (CL) and DNA polynucleotides
Poly [d(G-C)]- Poly[d(G-C)]

A) Without cardiolipin B) At DNA / CL ratio = 1:5

Poly[d(A-T)]-poly[d(A-T)]

A) Without cardiolipin B) At DNA / CL ratio = 1:5

 Summary of results we got for lipid binding to
DNA

• Lipids - fatty acids, cholesterol and its esters - interact with

DNA at minor groove with energy gain

• Lipid binding to DNA is sequence-specific. Lipids bind to AT-

rich DNA regions in recognition manner, an to CG-rich DNA
regions on a basis of saturation. The latter could be a
mechanism for stabilization of CG-repeats in non-coding
genome regions

• Linoleic acid binds to DNA more preferable compare to other

C18 acids

• Cariolipin-induced DNA assembly

 DNA-lipid recognition:

1. Neutral lipids (fatty acids, cholesterol) interact

prefearbly with dAT-rich DNA polynucleotides,
forming comlplexes which are stable in 60% aqueous
methanol (CD, DNA-chip,Chemosensor SensobiTM);

2. Cardiolipin interact with polydA*polyT DNA,

foming stable complexes (60% aqueous methanol)
(SensobiTM);

3. Phospholipids interact with dGdC-rich DNA

polynucleotides with higher energy gain (PC models).
 (PHOSPHO)LIPID - NUCLEIC ACID RECOGNITION
PHENOMENON
CONSEQUENCES:

• New mechanism of regulation of gene expression at

nuclear membrane and by lipids inside DNA double
helix
• Crystallization of DNA-(phospho)lipid membrane
complexes as model DNA-membrane contacts
• Natural lipid-DNA code of genome could exist, gene
expression and DNA-histone interaction being
modulated
• Additional informational level could exist in genomic
DNA, formed by lipids tightly bound to DNA
 DNA-lipid recognition:
• R. Zhdanov, B. Fedorov, P. Dyachkov (1997) DNA-phospholipid membrane rechgnition.
Theoretical consideration of of a new type of interactions between macromolecules of
biomedical importance. J. MOLECULAR MEDICINE (Berlin) v. 75, # 5, B2-B3.
• B. Fedorov, P. Dyachkov and R. Zhdanov (1999) DNA-Me (II) ions-PC complexes: structure
calculations and stability estimates by molecular mechanics. RUS. CHEM. BULLETIN v. 48,
#11, 2046-2049.
• P. D΄yachkov, B. Fedorov, R. Bischoff, G. Bischoff and R Zhdanov (2002) DNA – phospholipid
recognition: modulation by metal ion and lipid nature. Complexes structure and stability calculated
by molecular mechanics. BIOELECTROCHEM. v. 58, 47-51.
• Zhdanov R.I., Strazhevskaya N.B., Jdanov A., Bischoff G. (2002) A Spectroscopic and surface
plasmon resonance study of DNA/oleic acid complexes. J. BIOMOL. STR. DYNAMICS 20,
232-243.
• Zhdanov R., Dyachkov E.,Struckov V. et al (2003) Doklady Biochem. Biophys., 390, 548-552.
• Zhdanov R., Dyachkov E., Strazhevskaya N.B. et al(2003) RUS. CHEM. BULL., Int. Ed. 1794-
1800.
• Zhdanov R., Dyachkov E., Krylov A. et al (2005) Cholesterol and his esters in DNA:
biochemical analysis, PC modelling and DNA microarray. RUS. CHEM. BULL. 53, № 12.
• Bischoff G., Hoffmann S., Zhdanov R. (2004) DNA binding drugs used in medicinal therapies.
FROUNT. MED. CHEM. 1, # 1, 619-648.
• R. Zhdanov, S. Hombach-Klonisch, G. Bischoff (2005) Impact of Lipid-DNA Interaction, in:
“Micro- and Nanostructures of Biological Systems”, the 3d edition, G. Bischoff, ed. Shaker
Verlag, Aachen, 133-159.
 Nucleic Acid–Phospholipid (Membrane)
Recognition:

• Hypothesis (1994):
There is a relationship of the
interaction which is dependent
from nucleic acid bases‘
sequence, a nature of PhL‘
polar moiety and of Me (II)
cation.

Hypothesis and
Phenomena...
 STOICHIOMETRY OF DNA-PhL MEMBRANE
COMPLEXATION: DNA-Ca (II) ions-DPPC vesicles

ELECTRON MICROGRAPHS MODEL OF

PHENOMENON
STOICHIOMETRY OF DNA - Me(II) IONS -
PhL MEMBRANE COMPLEX

Mn/P ratio is 3 Pb/P ratio is 5

Basic principles of interaction between nucleic acids and
organized phospholipid surfaces (membranes):
• Local unwinding of DNA double helix in the presence of PhL vesicles and
Me (II) ions
• Only physiological cations Me (II) (Mg, Ca, Mn, Zn) can form stable
complexes with PhL and d.s. Nucleic acids
• D.s. nucleic acids can interact with PhL membranes even without Me (II)
ions
• There are 2 stages of DNA/RNA-Mg(II)-PhL complexing: fast
(dependent from Me (II) nature) and slow one
• The shorter Me ion radius, and the higher its redox potential, the higher
complexation
• PhL membranes disturb DNA low affinity Me binding sites (purine N7)
at major groove
• PhL membranes induce DNaes activty at 37oC and
Girase activity at 0oC in non-specific transcription system
 Gene pharmaceuticals for gene transfer and
therapy – one of the major current application of
lipids in pharmacy

Cationic lipids

Amphiphilic lipids

Helper lipids: DOPE, PC

Dicationic – germini – lipids

Cardiolipin – plasmid DNA delivery systems …

DLPE, but not DOPE as helper lipid as it follows
from in silico experiments…
 Structure of new
lipids - non-viral gene
delivery systems:
VI - CLYCOCLIP
VII–monoCHOLENIM
VIII – diCHOLENIM;
IX – triCHOLENIM
(cho=Cholesterol);
X – LacS, hydrophobic
lactose
XII - DEGA, dicationic
Lipids (germini)

R. Zhdanov et al.
Metods in Enzymology, 2003
 Formula of lipids used
CH3(CH2)7CH=CH(CH2)7COOH Oleic acid

Vitamin D2

Vitamin D3

Phosphatidyl
choline

New dicationic lipids

GEGA
Phase transitions of DNA, lipids and their complexes
А Tm
L Lα А. Self-assembling cationic liposomes and DNA
β‘ Fusion of vesicles and formation of
multilamellar aggregates with DNA
B
dDNA
B. Phase transition of DEGA lipid acyl residues
liquid crystal – gel

dL

Structure of lipoplexes between pDNA and dicationic lipids DEGA

А B

C D

А-C - DEGA-4, D- DEGA-7

 Structure of lipoplexes between pDNA and
dicationic lipids DEGA

А B

C D

А-C - DEGA-4, D - DEGA-7

 ICR mice lung histochemical preparations after administering pCMV-
SPORT-beta-Gal – PC/diCHOLENIM (1:1) lipoplex into liver vena porta,
Lac Z gene expression, X-Gal dye, AXIOSKOP 20 Carl Zeiss.
LacZ gene expression after administering pCMV-SPORT-beta-Gal –
PC/diCHOLENIM/LacS (1:1:0.1) lipoplex into liver vena porta, Lac
Z gene expression, X-Gal dye, AXIOSKOP 20 Carl Zeiss.

B
А - spleen,
B – liver

А
 Instead of conclusion

Very personal opinion:

“Medicine should be food, and food should be medicine”

Hippocratus

Outlooks:

“Food modeling and design”

Acknowledgements and Collaborations:

Germany
Dr. Gerlinde Bischoff, Prof. Dr. Wihelm Lorenz, Halle (S.),
Prof. Dr. Heinz Ruetherjans, Frankfurt/Main

Russia
Prof. Dr. Pavel Dyachkov, Moscow
Dr. Alex Krylov, Moscow
Dr. Anastasia Shmyrina, Moscow
Prof. Dr. Ahat Ilyasov, Kazan

Switzerland
Maxim Fedorovsky