Cholesterol and its fatty acid esters in native DNA preparations: lipid analysis, computer simulation of their interaction with DNA and cholesterol binding to immobilized oligodeoxyribonucleotides

Жданов, Р. И.; D’yachkov, E. P.; Strazhevskaya, N. B.; Shmyrina, A. S.; Крылов, А. С.; D’yachkov, P. N.; Lorenz, W.; Kubatiev, A. A.

doi:10.1007/s11172-006-0097-2

Cited by 6 publications

(3 citation statements)

References 11 publications

(22 reference statements)

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“…For mixed DNA sequences, the behavior is more complex. It has been shown that cholesterol and its esters can form stable complexes with DNA duplexes (72). Furthermore, inter-cholesterol hydrophobic interactions have been demonstrated to increase the melting temperature of nucleic acid duplexes and triplexes by up to 13°C and 30°C, respectively (73).…”

Section: Discussionmentioning

confidence: 99%

Controlling aggregation of cholesterol-modified DNA nanostructures

Ohmann

Göpfrich

Joshi

et al. 2019

Nucleic Acids Research

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DNA nanotechnology allows for the design of programmable DNA-built nanodevices which controllably interact with biological membranes and even mimic the function of natural membrane proteins. Hydrophobic modifications, covalently linked to the DNA, are essential for targeted interfacing of DNA nanostructures with lipid membranes. However, these hydrophobic tags typically induce undesired aggregation eliminating structural control, the primary advantage of DNA nanotechnology. Here, we study the aggregation of cholesterol-modified DNA nanostructures using a combined approach of non-denaturing polyacrylamide gel electrophoresis, dynamic light scattering, confocal microscopy and atomistic molecular dynamics simulations. We show that the aggregation of cholesterol-tagged ssDNA is sequence-dependent, while for assembled DNA constructs, the number and position of the cholesterol tags are the dominating factors. Molecular dynamics simulations of cholesterol-modified ssDNA reveal that the nucleotides wrap around the hydrophobic moiety, shielding it from the environment. Utilizing this behavior, we demonstrate experimentally that the aggregation of cholesterol-modified DNA nanostructures can be controlled by the length of ssDNA overhangs positioned adjacent to the cholesterol. Our easy-to-implement method for tuning cholesterol-mediated aggregation allows for increased control and a closer structure–function relationship of membrane-interfacing DNA constructs — a fundamental prerequisite for employing DNA nanodevices in research and biomedicine.

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Section: Discussionmentioning

confidence: 99%

Controlling aggregation of cholesterol-modified DNA nanostructures

Ohmann

Göpfrich

Joshi

et al. 2019

Nucleic Acids Research

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“…However, plants and microorganisms are endowed with numerous polycyclic aromatic phenolic compounds, glycosides, and alkaloids [15]. Additionally, though not planar in its native configuration, cholesterol and a plethora of metabolic derivatives of this compound, including sex hormones and steroids, can be aromatized to polycyclic derivatives that can covalently interact with DNA [16]. In this regard it is intriguing that Polk mRNA (but not Poli or Poll mRNA) is particularly highly expressed in the adrenal cortex of embryonic and adult mice, the site of steroid biosynthesis [17].…”

Section: Introductionmentioning

confidence: 99%

Polk mutant mice have a spontaneous mutator phenotype

et al. 2009

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Mice defective in the Polk gene (which encodes DNA polymerase kappa) are viable and do not manifest obvious phenotypes. The present studies document a spontaneous mutator phenotype in Polk−/− mice. The initial indication of enhanced spontaneous mutations in these mice came from the serendipitous observation of a postulated founder mutation that manifested in multiple disease states among a cohort of mice comprising all three possible Polk genotypes. Polk−/− and isogenic wild type controls carrying a reporter transgene (the λ-phage cII gene) were used for subsequent quantitative and qualitative studies on mutagenesis in various tissues. We observed significantly increased mutation frequencies in the kidney, liver, and lung of Polk−/− mice, but not in the spleen or testis. G:C base pairs dominated the mutation spectra of the kidney, liver, and lung. These results are consistent with the notion that Polκ is required for accurate translesion DNA synthesis past naturally occurring polycyclic guanine adducts, possibly generated by cholesterol and/or its metabolites.

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“…4 Fatty acids were shown to be stronger bound to the DNA minor groove than to the major groove. The energy of interactions between fatty acids and DNA was found to depend on the number of double bonds and the isomerism of fatty acids, as well as on the nucleotide composition of DNA.…”

mentioning

confidence: 99%

Simulation of interactions between DNA and diglycerides

et al. 2008

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Calculations by molecular mechanics methods showed that diglycerides containing stearic, oleic, linoleic, or linolenic acids can bind to DNA. The binding energy of diglycerides to the DNA minor groove is higher than that to the major groove. The bond energies of diglycerides to DNA were calculated as the sums of the contributions of the binding energies between DNA and two fatty acid residues. These energies depend on the structure of the fatty acid and the nucleotide composition of DNA and vary from 20 to 120 kcal mol -1 .In our previous studies, 1-3 we have used molecular mechanics methods to determine the structures and estimate the bond energies of DNA to saturated and unsaturated fatty acids containing 18 carbon atoms, viz., stearic (18:0), cis and trans isomers of oleic (18:1), linoleic (18:2), and linolenic (18:3) acids, as well as to cholesterol. 4 Fatty acids were shown to be stronger bound to the DNA minor groove than to the major groove. The energy of interactions between fatty acids and DNA was found to depend on the number of double bonds and the isomerism of fatty acids, as well as on the nucleotide composition of DNA. In another series of studies, we calculated the bond energies of phos phatidylcholine or sphingomyeline to 64 oligodeoxyribo nucleotides corresponding to triplets of the genetic code. 5,6 It was demonstrated that GC rich triplets form more stable complexes with phospholipids and that the complexes with sphingomyeline are characterized by higher energies.The present study continues our research on the com plexation of DNA with lipids by molecular mechanics methods. The aim was to investigate the character of in teractions and the bond energies of DNA to diglycerides containing stearic, trans oleic, cis oleic, trans,trans li noleic, cis,cis linoleic, trans,trans,trans linolenic, and cis,cis,cis linolenic acids. Calculation procedureAs in our earlier studies, 1-6 all calculations were per formed by the molecular mechanics method using the MM + force field and the Hyperchem 5.01 program package. In this method, the total energy E total of systems (complexes) is calculated as the sum of the contributions from bond length deformations, bond angle deformations, the torsional strain, the electrostatic interaction energy, the van der Waals (nonbonded) interaction energy, and the hydrogen bond energy. The full geometry optimization was carried out for fragments of the DNA double strand, diglycerides (Fig. 1), and the oligodeoxyribonucleotide (ON)-ligand complexes. The bond energies E bond of the ligands with ON were evaluated. The B form of ON was considered, and sodium ions were added to fulfill the electroneutrality condition.The bond energies of ON with the ligands were evalu ated as the difference between the total energy of the ON-diglyceride complex and the sum of the energies of the isolated components of the complex. Taking into account the geometric features of the DNA B form in terms of the double stranded model, the ligand (diglyceride) molecules were located in the minor or major gr...

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Cholesterol and its fatty acid esters in native DNA preparations: lipid analysis, computer simulation of their interaction with DNA and cholesterol binding to immobilized oligodeoxyribonucleotides

Cited by 6 publications

References 11 publications

Controlling aggregation of cholesterol-modified DNA nanostructures

Controlling aggregation of cholesterol-modified DNA nanostructures

Polk mutant mice have a spontaneous mutator phenotype

Simulation of interactions between DNA and diglycerides

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