Computational comparison of the stacking interactions between the aromatic amino acids and the natural or (cationic) methylated nucleobases

The strongest gas-phase MP2/6-31G*(0.25) stacking energies between the aromatic amino acids and the natural or methylated nucleobases were considered. The potential energy surfaces of dimers were searched as a function of the vertical separation, angle of rotation and horizontal displacement between monomers stacked according to their centers of mass. Our calculations reveal that the stacking interactions of adducts for a given nucleobase are dependent on the methylation site (by up to 20 kJ mol(-1)), where the relative magnitudes of the interactions are determined by the dipole moments of the adducts and the proton affinities of nucleobase methylation sites. Nevertheless, the differences in the (gas-phase) stacking of methylated adducts are small compared with the differences between the stacking of the corresponding natural and methylated nucleobases. Indeed, methylation increases the stacking energy by up to 40 kJ mol(-1) (or 135%). Although immersing the dimers in different solvents decreases the gas-phase stacking energies with an increase in the polarity of the environment, base methylation still has a significant effect on the nucleobase stacking ability in solvents with large dipole moments, and, perhaps more importantly, environments that mimic enzyme active sites. Our results shed light on the workings of DNA repairs enzymes that selectively remove a wide variety of alkylated nucleobases over the natural bases.     

Structural Properties of Hachimoji Nucleic Acids and Their Building Blocks: Comparison of Genetic Systems with Four,Six and Eight Alphabets

Expansion of the genetic alphabet is an ambitious goal. A recent breakthrough has led to the eight-base (hachimoji) genetics having canonical and unnatural bases. However, very little is known on the molecular-level features that facilitate the candidature of unnatural bases as genetic alphabets. Here we amalgamated DFT calculations and MD simulations to analyse the properties of the constituents of hachimoji DNA and RNA. DFT reveals the dominant syn conformation for isolated unnatural deoxyribonucleosides and at the 5′-end of oligonucleotides, although an anti/syn mixture is predicted at the nonterminal and 3′-terminal positions. However, isolated ribonucleotides prefer an anti/syn mixture, but mostly prefer anti conformation at the nonterminal positions. Further, the canonical base pairing combinations reveals significant strength, which may facilitate replication of hachimoji DNA. We also identify noncanonical base pairs that can better tolerate the substitution of unnatural pairs in RNA. Stacking strengths of 51 dimers reveals higher average stacking stabilization of dimers of hachimoji bases than canonical bases, which provides clues for choosing energetically stable sequences. A total of 14.4 μs MD simulations reveal the influence of solvent on the properties of hachimoji oligonucleotides and point to the likely fidelity of replication of hachimoji DNA. Our results pinpoint the features that explain the experimentally observed stability of hachimoji DNA.     

Functional monomers and polymers. CXXI. Methylation and interaction studies on adenine containing polymethacrylate derivatives

Studies of the methylation of polymethacrylate derivatives with adenine bases were made in comparison to those with uracil bases. The polymethacrylate derivatives with adenine bases were methylated by using methyl iodide in dimethyl sulfoxide solution to produce polymers that contained N¹-methyladenine and N¹, N⁶-dimethyladenine units. The products were identified by spectroscopic data and by preparing their model compounds. The methylated polymers obtained were further applied in a study of polymer complex formation with uracil-base polymers.     

DNA甲基化-非甲基化碱基间堆积作用的理论研究

运用二级Mфller-Plesset(MP2)理论方法和cc-pVDZ基组优化了6-甲基鸟嘌呤(O6-MethylG),4-甲基胸腺嘧啶(O4-MethylT)以及5-甲基胞嘧啶(C5-MethylC)与DNA碱基鸟嘌呤(G),腺嘌呤(A),胞嘧啶(C),胸腺嘧啶(T)之间的堆积构型.在MP2/aug-cc-pVXZ//MP2/cc-pVDZ(X=D,T)水平上,采用完全基组外推方法校正了堆积碱基对间的相互作用能,并用完全均衡校正法(CP)校正了基组重叠误差(BSSE).MP2计算结果表明,DNA碱基甲基化使得嘧啶-嘧啶、嘧啶-嘌呤堆积碱基间的平行旋转角发生明显改变,并使堆积碱基间的相互作用能增大.在MP2/cc-pVDZ计算级别上得到了各堆积碱基对的全电子波函数,并用分子中的原子理论(AIM)分析了堆积碱基对间的弱相互作用.AIM分析结果显示,甲基化增强了堆积碱基间的π-π作用,且甲基氢与相邻碱基间形成H2CH…X(X=O,N,CH3,NH2)等类型的氢键.甲基化损伤使碱基间重叠程度增大、π-π作用增强以及堆积碱基间形成多个氢键,是堆积作用能增加的主要原因.     

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.     

Comprehensive study of the effects of methylation on tautomeric equilibria of nucleic acid bases

Minor tautomers of nucleic acid bases can result by intramolecular proton transfer. These rare tautomers could be stabilized through the addition of methyl groups to DNA bases. A comprehensive theoretical study of tautomers of methylated derivatives of guanine, adenine, cytosine, thymine, and uracil was performed. Molecular geometries of all tautomers were obtained at the density functional theory and MP2 levels with the 6-31G(d,p) basis set, and single-point calculations were performed at the CCSD(T)/6-311G(d,p) level. Tautomers obtained by protonation at the preferred protonation site for methylated isolated bases were compared to their nonmethylated counterparts. The effects of methylation on the relative stabilities of nucleic acid base tautomers are also studied and discussed in this work. The results suggest that some sites on the bases may not be mutagenic and may even stabilize the canonical Watson-Crick form. The results also indicate that a number of methylation sites can stabilize the tautomers, suggesting possible mechanisms for mutagenic changes.     

Toward true DNA base-stacking energies: MP2, CCSD(T), and complete basis set calculations

Stacking energies in low-energy geometries of pyrimidine, uracil, cytosine, and guanine homodimers were determined by the MP2 and CCSD(T) calculations utilizing a wide range of split-valence, correlation-consistent, and bond-functions basis sets. Complete basis set MP2 (CBS MP2) stacking energies extrapolated using aug-cc-pVXZ (X = D, T, and for pyrimidine dimer Q) basis sets equal to -5.3, -12.3, and -11.2 kcal/mol for the first three dimers, respectively. Higher-order correlation corrections estimated as the difference between MP2 and CCSD(T) stacking energies amount to 2.0, 0.7, and 0.9 kcal/mol and lead to final estimates of the genuine stacking energies for the three dimers of -3.4, -11.6, and -10.4 kcal/mol. The CBS MP2 stacking-energy estimate for guanine dimer (-14.8 kcal/mol) was based on the 6-31G(0.25) and aug-cc-pVDZ calculations. This simplified extrapolation can be routinely used with a meaningful accuracy around 1 kcal/mol for large aromatic stacking clusters. The final estimate of the guanine stacking energy after the CCSD(T) correction amounts to -12.9 kcal/mol. The MP2/6-31G(0.25) method previously used as the standard level to calculate aromatic stacking in hundreds of geometries of nucleobase dimers systematically underestimates the base stacking by ca. 1.0-2.5 kcal/mol per stacked dimer, covering 75-90% of the intermolecular correlation stabilization. We suggest that this correction is to be considered in calibration of force fields and other cheaper computational methods. The quality of the MP2/6-31G(0.25) predictions is nevertheless considerably better than suggested on the basis of monomer polarizability calculations. Fast and very accurate estimates of the MP2 aromatic stacking energies can be achieved using the RI-MP2 method. The CBS MP2 calculations and the CCSD(T) correction, when taken together, bring only marginal changes to the relative stability of H-bonded and stacked base pairs, with a slight shift of ca. 1 kcal/mol in favor of H-bonding. We suggest that the present values are very close to ultimate predictions of the strength of aromatic base stacking of DNA and RNA bases.     

核酸碱基的非谐性振动:Ⅲ,DNA叠加二聚体的一维和二维红外光谱

用量子化学计算方法研究了DNA碱基单体及其15个B型和2个G-四链体的叠加二聚体的非谐性振动光谱特征.研究发现,从碱基单体到二聚体,C=O伸缩模式之间的相互作用很强,表现在其非谐性振动频率和非谐性常数都发生了明显的改变,特别是在含碱基G的叠加体中.这些变化能在一维和二维红外光谱中很好地表现出来.利用振动模式的势能分布和非谐性常数的组成分析,讨论了叠加二聚体中C=O模式的离域化程度.     

Synthesis and antibacterial activity of methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride

The methylated chitosan containing different aromatic moieties were synthesized by two steps, the reductive amination and the methylation. The chemical structures of all methylated derivatives, methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride (MDMCMCh), methylated N-(4-pyridylmethyl) chitosan chloride (MPyMeCh), and N,N,N-trimethyl chitosan chloride (TMChC) were characterized by ATR-FTIR and ¹H NMR spectroscopy. The molecular weights of the methylated chitosan derivatives were determined by gel permeation chromatography. The results revealed that the molecular weights of chitosan and N-aryl chitosan derivatives could be reduced by the methylation process. The degree of N-substitution (DS) and the degree of quaternization (DQ) were calculated by ¹H NMR ranged from 50% to 76%, and 28% to 82%, respectively. The water solubility of the methylated chitosan derivatives decreased with increasing concentration and pH. The antibacterial studies of these methylated chitosan derivatives were carried out by using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods against Escherichia coli ATCC 25922 (Gram-negative) and Staphylococcus aureus ATCC 6538 (Gram-positive) bacteria. It was found that the MDMCMCh showed higher antibacterial activity than TMChC while MPyMeCh exhibited reduced antibacterial activity against both bacteria at the same DQ level. In comparison to each of the chemical structure, it was found that the antibacterial activity was not only dependent on the DQ but it was also dependent on the positively charged location and the molecular weight.     

High‐Resolution Crystal Structure of a Silver(I)–RNA Hybrid Duplex Containing Watson–Crick‐like CSilver(I)C Metallo‐Base Pairs

Metallo‐base pairs have been extensively studied for applications in nucleic acid‐based nanodevices and genetic code expansion. Metallo‐base pairs composed of natural nucleobases are attractive because nanodevices containing natural metallo‐base pairs can be easily prepared from commercially available sources. Previously, we have reported a crystal structure of a DNA duplex containing T? Hg^II? T base pairs. Herein, we have determined a high‐resolution crystal structure of the second natural metallo‐base pair between pyrimidine bases C? Ag^I? C formed in an RNA duplex. One Ag^I occupies the center between two cytosines and forms a C? Ag^I? C base pair through N3? Ag^I? N3 linear coordination. The C? Ag^I? C base pair formation does not disturb the standard A‐form conformation of RNA. Since the C? Ag^I? C base pair is structurally similar to the canonical Watson–Crick base pairs, it can be a useful building block for structure‐based design and fabrication of nucleic acid‐based nanodevices.     

High‐Resolution Crystal Structure of a Silver(I)–RNA Hybrid Duplex Containing Watson–Crick‐like C?Silver(I)?C Metallo‐Base Pairs

Metallo‐base pairs have been extensively studied for applications in nucleic acid‐based nanodevices and genetic code expansion. Metallo‐base pairs composed of natural nucleobases are attractive because nanodevices containing natural metallo‐base pairs can be easily prepared from commercially available sources. Previously, we have reported a crystal structure of a DNA duplex containing T Hg^II T base pairs. Herein, we have determined a high‐resolution crystal structure of the second natural metallo‐base pair between pyrimidine bases C Ag^I C formed in an RNA duplex. One Ag^I occupies the center between two cytosines and forms a C Ag^I C base pair through N3 Ag^I N3 linear coordination. The C Ag^I C base pair formation does not disturb the standard A‐form conformation of RNA. Since the C Ag^I C base pair is structurally similar to the canonical Watson–Crick base pairs, it can be a useful building block for structure‐based design and fabrication of nucleic acid‐based nanodevices.     

Functional monomers and polymers. CX. Methylation and interaction studies on uracil-containing polymethacrylate derivatives

A polymethacrylate derivative containing uracil bases was methylated by using methyl iodide or dimethyl sulfate to give polymers containing 3-methyluracil derivatives. In the case of methylation with dimethyl sulfate, sulfonation at 5-position of the bases occurred in addition to the methylation at N-3 position. The methylated polymers thus obtained were used further for the study of polymer complex formation with polymethacrylate containing adenine base.     

Genomic N(6)-methyladenine determination by MEKC with LIF

2′‐Deoxy‐N⁶‐methyladenosine (N⁶mdA) is frequently found in prokaryotic and unicellular eukaryotic genomes. Although methylated bases represent only a minor fraction of the genome, they, however, exhibit strong biological effects. Here, we report a fast and sensitive method for the quantification of global adenine methylation in DNA. The method is based on a recently developed procedure consisting of fluorescence labeling of deoxyribonucleotides with BODIPY FL EDA and analysis by CE with LIF. An oligodeoxyribonucleotide site specifically modified with N⁶mdA was used for peak assignment, to establish separation conditions and to determine the LOD. The method yielded a LOD for N⁶mdA of 280 pM (1.4 amol), which is equivalent to ～1 N⁶mdA per 10⁴ normal nucleotides (0.01%) using 1 μg of DNA as the matrix. After calibration with completely dam methylated λ DNA, the assay was applied to the analysis of various DNAs.     

Umamidierungsreaktionen an cyclischen Amino-amid-Systemen. 3. Mitteilung über Umamidierungsreaktionen

Transamidation Reactions with Cyclic Amino-amides Lactames which are substituted at the nitrogen atom by a 3-aminopropyl residue are transformed under base catalysis to cyclic amino-amides enlarged by 4 ring atoms. The formed ring must be at minimum 12-membered. Scheme 2 illustrates this result: the 8-membered 7 is transamidated in 96% yield to the 12-membered ring 8 (in the presence of potassium 3-aminopropylamid in 1, 3-propanediamine), the 9-membered 10 to the 13-membered ring 11 (97%) and the 11-membered 14 to the 15-membered ring 15 . Furthermore, the 13-membered ring 27 (Scheme 5) is transformed to the 17-membered 28 . In the case of the 15-membered lactame 15 it is demonstrated that 14 is not formed back under the conditions of the transamidation. Large ring lactames which are substituted at the nitrogen atom by a 3-(alkylamino) propyl group lead under base catalysis to an equilibrium mixture, e.g. the 17-membered 26 is in equilibrium with the 21-membered 29 . This result is similar to the behavior of the corresponding open-chain amino-amides [2]. Because of transannular interactions, the 11-membered ring 2 is not stable: transamidation of the 7-membered 1 (Scheme 1) doesn't give the expected 2 , but its water elimination product 3 in small yield. The N-tosyl derivative of 2 , namely 20 , is synthesized by an independent route (Scheme 3). Detosylation of 20 yields the 7-membered 1 instead of 2 . Concerning the mechanism of this interesting reaction see Scheme 4.     

Synthesis, crystal structure and bioactivity of a novel 18-metallacrown-6 [Mn6(H2O)6 (anshz)6] · 10DMF

A novel macrocyclic hexanuclear manganese(III) 18-metallacrown-6 compound, [Mn₆(H₂O)₆ (anshz)₆] · 10DMF, has been prepared using a trianionic pentadentate ligand N-acetyl-5-nitrosalicylhydrazide (anshz³⁻) and characterized by X-ray diffraction (DMF = N,N-dimethylformamide). The crystal structure contains a neutral 18-membered metallacrown ring consisting of six Mn(III) and six anshz³⁻ ligands. The 18-membered metallacrown ring is formed by the succession of six structural moieties of the type [Mn(III)NN]. Due to the meridional coordination of the ligand to the Mn³⁺ ion, the ligand enforces the stereochemistry of the Mn³⁺ ions as a propeller configuration with alternating Δ/Λ forms. The disc-shaped hexanuclear ring shows at its largest diameter about 7.14 Å at entrance, about 9.76 Å at the center of the cavity, respectively. Antibacterial screening data showed that the manganese metallacrown has strong antimicrobial activity against Bacillus subtilis.     

Assessment of intermolecular N–H…F and N–H…Cl hydrogen bonding in stabilising hetero- and homodimers in solution

This paper describes the first assessment of intermolecular weak N–H…F and N–H…Cl hydrogen bonding in stabilising hetero- and homodimers in solution. Aromatic amide and urea monomers have been designed and synthesised. The association constants of the heterodimers formed by two complementary monomers and the homodimers formed by self-complementary monomers have been determined by using ¹H titration and dilution experiments. The results show that both N–H…F and N–H…Cl hydrogen bonds are able to stabilise the corresponding dimers to a measurable extent, even though the stability of the dimers is generally low.     

Synthesis, X-ray structures, and catalytic applications of palladium(II) complexes bearing N-heterocyclic iminocarbene ligands

Two new Pd(II) N-heterocyclic iminocarbene complexes (C-N)PdCl₂ that contain 5-membered chelate rings have been prepared by carbene transfer from a silver iminocarbene precursor to (COD)PdCl₂. The new Pd imonocarbene complexes, as well as two that have been previously reported (altogether three 5-membered and one 6-membered chelate ring complexes) have been evaluated as catalysts for the Suzuki-Miyaura coupling reaction. The complexes were found to be active in the reaction, but without exceptional catalytic performances. The 5-membered chelate ring complexes appeared to be more robust and remained active for a longer time than the 6-membered ring congener. The catalytic performance of the 5-membered chelate ring complexes appeared to be rather insensitive to the steric demands of the imine-N-aryl group. The X-ray structure of one of the Ag iminocarbene complexes reveals the κ¹(C) bonding of the iminocarbene moiety in a nearly linear Ag(I) complex; two monomeric units are associated through a weak Ag-Ag interaction. The X-ray structures of two new Pd iminocarbene complexes (C-N)PdCl₂ confirm the chelating κ²(C,N) nature of the iminocarbene moiety; in both complexes, the Pd-Cl distances trans to carbene-C are slightly longer than those trans to imine-N.     

3‐[(E)‐(3‐tert‐Butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)iminomethyl]quinolin‐2(1H)‐one: chains built by π‐stacking of hydrogen‐bonded R22(8) dimers

In the title compound, C₂₃H₂₂N₄O, there is evidence for some bond fixation in the aryl component of the quinolinone unit. Pairs of molecules related by inversion are linked into R₂²(8) dimers by almost linear N—H...O hydrogen bonds, and dimers related by inversion are linked into chains by a single aromatic π–π stacking interaction.     

Synthesis and optical properties of polyethylenimine containing L-proline and optically active thymine derivatives

Preparation and optical properties of linear polyethylenimine (PEI) containing L -(?)-N-[(?)-2-(thymin-1-yl) propionyl] prolyl group as grafting pendant, [P-(?)Pro-(?)T], and its related monomer and dimer model compounds are described. Hypochromic effects and circular dichroism of these compounds were compared with those of PEI containing (?)-2-(thymin-1-yl) propionyl group as grafting pendant, [P-(?)T], which has no L -proline ring as a spacing group. P-(?)Pro-(?)T showed no exciton coupling of B_2u π-π^* transition although it showed large hypochromicity in neutral aqueous solution, implying that the stacking of the bases has no screw sense.