Structure of a copper-mediated base pair in DNA.

Stable and selective DNA base pairing by metal coordination was recently demonstrated with nucleotides containing complementary pyridine-2,6-dicarboxylate (Dipic) and pyridine (Py) bases (Meggers, E.; Holland, P. L.; Tolman; W. B.; Romesberg, F. E.; Schultz, P. G. J. Am. Chem. Soc. 2000, 122, 10714-10715). To understand the structural consequences of introducing this novel base pair into DNA we have solved the crystal structure of a duplex containing the metallo-base pair. The structure shows that the bases pair as designed, but in a Z-DNA conformation. The structure also provides a structural explanation for the B- to Z-DNA transition in this duplex. Further solution studies demonstrate that the metallo-base pair is compatible with Z- or B-DNA conformations, depending on the duplex sequence.     

A theoretical study on the hydration of B- and Z-DNA double helices

A theoretical study on the hydration of B- and Z-DNA double helices has been carried out using empirical potential energy functions. The interaction energy between water and the model compounds has been computed considering only the first hydration shell.The results show the number of binding water molecules to be thirty-six and twenty-five in B- and in Z-DNA, respectively. The water molecules in the first hydration shell of B-DNA are very well ordered along the phosphate groups of the backbone whereas those of Z-DNA are more disordered than in B-DNA and are more strongly bound. The water molecules near the first hydration shell of Z-DNA are thought to move more freely than those of B-DNA.     

One-electron attachment reaction of B- and Z-DNA modified by 8-bromo-2'-deoxyguanosine

The one-electron attachment reaction of 8-bromo-2'-deoxyguanosine ((Br)G) in DNA was studied by comparing that in B- and Z-DNA. Oligodeoxynucleotides (ODNs) modified by (Br)G were synthesized as Z-DNA in which the syn-conformation deoxyguanosine is stabilized by steric interference between the 8-bromo group of (Br)G and the sugar moiety. Debromination from the (Br)G-modified ODNs occurred from the one-electron attachment during the gamma-radiolysis. The structural dependence of B- and Z-DNA was observed for the one-electron attachment reaction. The conversion of (Br)G was higher in Z-DNA than in B-DNA. Because the solvent-accessible surface of the purine base in Z-DNA is greater than that in B-DNA, it is demonstrated that the reactivity of purine base C8 is enhanced in Z-DNA compared to that in B-DNA.     

An ab initio molecular orbital study on the stacking interaction between nucleic acid bases: Dependence on the sequence and relation to the conformation

The stacking interaction energies between nucleic acid bases in A DNA and B DNA are calculated by means of the ab initio molecular orbital method. The calculated values agree well with the experimental values of stacking enthalpy changes. The stacking interaction energy is shown to be highly sequence dependent, particularly when the sequence includes guanine or cytosine. The possibility is shown that the conformation of a DNA double helix fragment is determined by the constituent stacking interaction. Electrostatic energy is the cause of the sequence dependency of the stacking energy, while charge transfer and dispersion energies contribute to the overall stability.     

Investigation of the stability of oligonucleotides and oligodinucleotides

The mutually-consistent-field (MCF) method together with pseudo polarization tensors has been employed to investigate in detail the intra- and inter-strand interactions in B-DNA helices. Results are reported for all four periodic homo-oligonucleotides showing that these configurations are stable only in the case of adenine and thymine. All the oligodinucleotides studied are stable, but the role of the different contributions, e.g. the two intrastrand and the interstrand interactions is dependent on the nucleotide bases. In the case of periodic guanine-cytosine base pairs, the interstrand energy is dominant, whereas in the corresponding alternating systems all three contributions are attractive. The stability of adenine-thymine systems is less sensitive with respect to periodic and alternating compositions.     

A computational proposal for the experimentally observed discriminatory behavior of hypoxanthine, a weak universal nucleobase

A computational model composed of six nucleobases was used to investigate why hypoxanthine does not yield duplexes of equal stability when paired opposite each of the natural DNA nucleobases. The magnitudes of all nearest-neighbor interactions in a DNA helix were calculated, including hydrogen-bonding, intra- and interstrand stacking interactions, as well as 1-3 intrastrand stacking interactions. Although the stacking interactions in DNA relevant arrangements are significant and account for at least one third of the total stabilization energy in our nucleobase complexes, the trends in the magnitude of the stacking interactions cannot explain the relative experimental melting temperatures previously reported in the literature. Furthermore, although the total hydrogen-bonding interactions explain why hypoxanthine preferentially pairs with cytosine, the experimental trend for the remaining nucleobases (A, T, G) is not explained. In fact, the calculated pairing preference of hypoxanthine matches that determined experimentally only when the sum of all types of nearest-neighbor interactions is considered. This finding highlights a strong correlation between the relative magnitude of the total nucleobase-nucleobase interactions and measured melting temperatures for DNA strands containing hypoxanthine despite the potential role of other factors (including hydration, temperature, sugar-phosphate backbone). By considering a large range of sequence combinations, we reveal that the binding preference of hypoxanthine is strongly dependent on the nucleobase sequence, which may explain the varied ability of hypoxanthine to universally bind to the natural bases. As a result, we propose that future work should closely examine the interplay between the dominant nucleobase-nucleobase interactions and the overall strand stability to fully understand how sequence context affects the universal binding properties of modified bases and to aid the design of new molecules with ambiguous pairing properties.     

Low-energy electron diffraction and induced damage in hydrated DNA

Elastic scattering of 5-30 eV electrons within the B-DNA 5'-CCGGCGCCGG-3' and A-DNA 5'-CGCGAATTCGCG-3' DNA sequences is calculated using the separable representation of a free-space electron propagator and a curved wave multiple scattering formalism. The disorder brought about by the surrounding water and helical base stacking leads to a featureless amplitude buildup of elastically scattered electrons on the sugar and phosphate groups for all energies between 5 and 30 eV. However, some constructive interference features arising from diffraction are revealed when examining the structural waters within the major groove. These appear at 5-10, 12-18, and 22-28 eV for the B-DNA target and at 7-11, 12-18, and 18-25 eV for the A-DNA target. Although the diffraction depends on the base-pair sequence, the energy dependent elastic scattering features are primarily associated with the structural water molecules localized within 8-10 A spheres surrounding the bases and/or the sugar-phosphate backbone. The electron density buildup occurs in energy regimes associated with dissociative electron attachment resonances, direct electronic excitation, and dissociative ionization. Since diffraction intensity can be localized on structural water, compound H2O:DNA states may contribute to energy dependent low-energy electron induced single and double strand breaks.     

柔红霉素与DNA作用的序列特异性研究

采用紫外-可见光谱法和紫外-可见光谱电化学法研究了柔红霉素(DNR)与不同寡聚核苷酸之间的相互作用.结果表明,DNR优先作用于寡聚核苷酸的CpG位点,然后是ApG和ApC.因为DNR可与鸟嘌呤之间形成3个氢键.与双链寡聚核苷酸作用时,DNR最先插入的位点是(CpG)₂碱基对之间,其次是(TpG)(CpA)和(GpC)(ApC)碱基对之间.当DNR与存在未配对G碱基的DNA链作用时,因游离的DNR量增加使其电化学活性增加,导致DNA构象和构型的变化,使DNA生理功能受到损伤,DNA碱基增色效应显著上升.此法可用于G碱基未配对DNA链的检测.     

Probing the microenvironments in the grooves of Z-DNA using dan-modified oligonucleotides

The environment-sensitive fluorophore dan (6-dimethylamino-2-acyl-naphthalene)- modified dC or dG bases were introduced into the Z-DNA forming sequence. It was demonstrated that both grooves of Z-DNA are more hydrated than those of B-DNA. Dan will be useful for probing the microenvironments in the grooves among the DNA polymorphs.     

Solution structure of a DNA duplex containing a biphenyl pair

Hydrogen-bonding and stacking interactions between nucleobases are considered to be the major noncovalent interactions that stabilize the DNA and RNA double helices. In recent work we found that one or multiple biphenyl pairs, devoid of any potential for hydrogen bond formation, can be introduced into a DNA double helix without loss of duplex stability. We hypothesized that interstrand stacking interactions of the biphenyl residues maintain duplex stability. Here we present an NMR structure of the decamer duplex d(GTGACXGCAG) d(CTGCYGTCAC) that contains one such X/Y biaryl pair. X represents a 3',5'-dinitrobiphenyl- and Y a 3',4'-dimethoxybiphenyl C-nucleoside unit. The experimentally determined solution structure shows a B-DNA duplex with a slight kink at the site of modification. The biphenyl groups are intercalated side by side as a pair between the natural base pairs and are stacked head to tail in van der Waals contact with each other. The first phenyl rings of the biphenyl units each show tight intrastrand stacking to their natural base neighbors on the 3'-side, thus strongly favoring one of two possible interstrand intercalation structures. In order to accommodate the biphenyl units in the duplex the helical pitch is widened while the helical twist at the site of modification is reduced. Interestingly, the biphenyl rings are not static in the duplex but are in dynamic motion even at 294 K.     

Iso-energy contour maps for the interaction of water with DNA double helix in the B conformation

The interaction energy between water with B-DNA double helix is computed for few cylindrical surfaces (enclosing the helix) using analytical pair potentials. The iso-energy contour maps indicate a strong attraction for water extending to three water layers surrounding DNA and very stable bridging structure of water molecules connecting two successive phosphate groups along a single helix in the innermost layer.     

Analysis of stacking overlap in nucleic acid structures: algorithm and application

RNA contains different secondary structural motifs like pseudo-helices, hairpin loops, internal loops, etc. in addition to anti-parallel double helices and random coils. The secondary structures are mainly stabilized by base-pairing and stacking interactions between the planar aromatic bases. The hydrogen bonding strength and geometries of base pairs are characterized by six intra-base pair parameters. Similarly, stacking can be represented by six local doublet parameters. These dinucleotide step parameters can describe the quality of stacking between Watson–Crick base pairs very effectively. However, it is quite difficult to understand the stacking pattern for dinucleotides consisting of non canonical base pairs from these parameters. Stacking interaction is a manifestation of the interaction between two aromatic bases or base pairs and thus can be estimated best by the overlap area between the planar aromatic moieties. We have calculated base pair overlap between two consecutive base pairs as the buried van der Waals surface between them. In general, overlap values show normal distribution for the Watson–Crick base pairs in most double helices within a range from 45 to 50 Å² irrespective of base sequence. The dinucleotide steps with non-canonical base pairs also are seen to have high overlap value, although their twist and few other parameters are rather unusual. We have analyzed hairpin loops of different length, bulges within double helical structures and pseudo-continuous helices using our algorithm. The overlap area analyses indicate good stacking between few looped out bases especially in GNRA tetraloop, which was difficult to quantitatively characterise from analysis of the base pair or dinucleotide step parameters. This parameter is also seen to be capable to distinguish pseudo-continuous helices from kinked helix junctions.     

Effect of loop distortion on the stability and structural dynamics of DNA hairpin and dumbbell conjugates

The thermal stability and conformational dynamics of DNA hairpin and dumbbell conjugates having short A-tract base pair domains connected by tri- or hexa(ethylene glycol) linkers is reported. The formation of stable base-paired A-tract hairpins having oligo(ethylene glycol) linkers requires a minimum of four or five A-T base pairs. The formation of base-paired dumbbells having oligo(ethylene glycol) linkers by means of chemical ligation of nicked dumbbells requires a minimum of two A-T base pairs on either side of the nick. Molecular modeling indicates that the hexa(ethylene glycol) linker is sufficiently long to permit formation of strain-free loop regions and B-DNA base pair domains. In contrast, the tri(ethylene glycol) is too short to permit Watson-Crick base pairing between the bases attached to the linker. The shorter linker distorts the duplex, resulting in fluxional behavior in which the base pairs adjacent to the linker and at the open end of the hairpin dissociate on the nanosecond time scale. The loss of interstrand binding energy caused by these fluctuations leads to a difference of approximately 5 degrees C in melting temperature between EG3 and EG6 hairpins. An analysis of the fluxional behavior of the EG3 adjacent base-pair has been used to study the pathways for base flipping and base stacking, including the identification of rotated base (partially flipped) intermediates that have not been described previously for A-T base pairs.     

Potential-derived point-charge model study of electrostatic interactions in DNA base components

Ab initio electrostatic potentials obtained using STO-3G wavefunctions for guanine, cytosine, adenine, and thymine are used to calculate potential-derived (PD) point charges for these base components. Calculated PD point charges are used to estimate the electrostatic contributions to hydrogen-bonding and stacking interaction energies of ten sequence isomers of B-DNA. These estimates are in excellent agreement with the results of the more elaborate segmental multipole moment expansion technique.     

DNA中的B-Z"链接"

DNA能够通过改变自身的构象来完成它在生命过程中的一些重要作用。在进行转录和其它一些生理过程中,B-DNA的局部区域会转变为Z-DNA,形成具有两个B-Z接合点的奇特的B-DNA-Z-DNA-B-DNA结构,在每个接合点处有一对碱基的氢键发生断裂且碱基被挤出而连接在双螺旋的外侧。探讨这种结构的形成机制对于理解DNA的结构与功能的关系具有重要意义,也将有助于更深刻地认识Z-DNA所扮演的角色。     

Insights into DNA binding of ruthenium arene complexes: role of hydrogen bonding and pi stacking

Density functional theory (DFT) methods are used to investigate the binding of ruthenium arene complexes, proposed as promising anticancer drugs, to isolated nucleobases. This shows a clear preference for binding at guanine over any other base and an approximately 100 kJ mol (-1) difference in binding between guanine and adenine in the gas phase, while binding to cytosine and inosine are intermediate in energy between these extremes. Solvation reduces binding energies and the discrimination between bases but maintains the overall pattern of binding. DFT and ab initio data on arene-base interactions in the absence of ruthenium show that stacking and hydrogen-bonding interactions play a significant role but cannot account for all of the energy difference between bases observed. Atoms-in-molecules analysis allows further decomposition of binding energies into contributions from covalent-binding, hydrogen-bonding, and pi-stacking interactions. Larger arenes undergo stabilizing stacking interactions, whereas N-H...X hydrogen bonding is independent of arene. Pairing of guanine to cytosine is affected by ruthenium complexation, with individual hydrogen-bonding energies being altered but the overall pairing energy remaining almost constant.     

非共价作用对气相中B-DNA双螺旋结构稳定性的贡献:基于GEBF方法的密度泛函理论计算

采用密度泛函理论, 将基于能量的分子片方法(GEBF)应用于气相中优化B型脱氧核糖核酸(碱基对数目N=2, 5, 10)双螺旋构型的结构. 通过比较M06-2X泛函和其他方法(B3LYP、B3LYP-vdW和TPSS泛函)的结果, 发现不考虑碱基之间的π-π堆积作用将会导致碱基之间的纵向距离拉长. 随着体系双螺旋链长的增加, 没有考虑碱基堆积作用而导致的相邻碱基纵向距离拉长的程度快速衰减. 计算表明, 气相中B-DNA双螺旋结构的稳定性来源于其作用力(主要是氢键和π-π堆积作用)的协同性, 对不多于10组碱基对的体系而言, 其氢键的贡献明显大于碱基堆积作用.     

Probing the B-to-Z-DNA duplex transition using terminally stacking ethynyl pyrene-modified adenosine and uridine bases

Pyrene-modified adenosine and uridine bases located in the dangling positions of G,C-alternating oligodeoxynucleotides undergo pi-stacking in their B-DNA duplexes, but not in their Z-DNA duplexes; fluorescence quenching in the former, through photoinduced electron transfer, but not in the latter, allows the state of the B-to-Z-DNA transition to be characterized visually.     

The base sequence dependent flexibility of linear single-stranded oligoribonucleotides correlates with the reactivity of the phosphodiester bond

The effect of base sequence on the structure and flexibility of linear single-stranded RNA molecules and the influence of the base sequence on phosphodiester bond reactivity have been studied. Molecular dynamics simulations of 2.1 ns were carried out for nine chimeric oligonucleotides containing only one unsubstituted ribo unit, all the rest of sugars being 2'-O-methylated. The base sequence has recently been reported to make a big contribution to the reactivity of these compounds. A detailed examination of the interaction energies between the base moieties shows that base stacking is strongly context-dependent and cooperative. The strength of stacking at the site susceptible to chain cleavage by intramolecular transesterification was observed to be dependent on both the flanking bases of the cleavage site and those further apart in the molecule. The interaction energies between the bases in the vicinity of the scissile linkage were found to correlate well with the experimental phosphodiester bond cleavage rates: the stronger the bases close to the cleavage site are stacked, the slower the cleavage rate is.