Atomistic understanding of the C·T mismatched DNA base pair tautomerization via the DPT: QM and QTAIM computational approaches

It was established that the cytosine·thymine (C·T) mismatched DNA base pair with cis‐oriented N1H glycosidic bonds has propeller‐like structure (|N3C4C4N3| = 38.4°), which is stabilized by three specific intermolecular interactions–two antiparallel N4H…O4 (5.19 kcal mol^?1) and N3H…N3 (6.33 kcal mol^?1) H‐bonds and a van der Waals (vdW) contact O2…O2 (0.32 kcal mol^?1). The C·T base mispair is thermodynamically stable structure (ΔG_int = ?1.54 kcal mol^?1) and even slightly more stable than the A·T Watson–Crick DNA base pair (ΔG_int = ?1.43 kcal mol^?1) at the room temperature. It was shown that the C·T ? C*·T* tautomerization via the double proton transfer (DPT) is assisted by the O2…O2 vdW contact along the entire range of the intrinsic reaction coordinate (IRC). The positive value of the Grunenberg's compliance constants (31.186, 30.265, and 22.166 Å/mdyn for the C·T, C*·T*, and TS_{C·T ? C*·T*}, respectively) proves that the O2…O2 vdW contact is a stabilizing interaction. Based on the sweeps of the H‐bond energies, it was found that the N4H…O4/O4H…N4, and N3H…N3 H‐bonds in the C·T and C*·T* base pairs are anticooperative and weaken each other, whereas the middle N3H…N3 H‐bond and the O2…O2 vdW contact are cooperative and mutually reinforce each other. It was found that the tautomerization of the C·T base mispair through the DPT is concerted and asynchronous reaction that proceeds via the TS_{C·T ? C*·T*} stabilized by the loosened N4? H? O4 covalent bridge, N3H…N3 H‐bond (9.67 kcal mol^?1) and O2…O2 vdW contact (0.41 kcal mol^?1). The nine key points, describing the evolution of the C·T ? C*·T* tautomerization via the DPT, were detected and completely investigated along the IRC. The C*·T* mispair was revealed to be the dynamically unstable structure with a lifetime 2.13·× 10^?13 s. In this case, as for the A·T Watson–Crick DNA base pair, activates the mechanism of the quantum protection of the C·T DNA base mispair from its spontaneous mutagenic tautomerization through the DPT. © 2013 Wiley Periodicals, Inc.     

Nanoswitches based on DNA base pairs: why adenine-thymine is less suitable than guanine-cytosine.

Substituted Watson–Crick guanine–cytosine (GC) base pairs were recently shown to yield robust three‐state nanoswitches. Here, we address the question: Can such supramolecular switches also be based on Watson–Crick adenine‐thymine (AT) base pairs? We have theoretically analyzed AT pairs in which purine‐C8 and/or pyrimidine‐C6 positions carry a substituent X=NH^?, NH₂, NH₃⁺ (N series), O^?, OH or OH₂⁺ (O series), using the generalized gradient approximation (GGA) of density functional theory at the BP86/TZ2P level. Thus, we explore the trend in geometrical shape and hydrogen bond strengths in AT pairs along a series of stepwise protonations of the substituents. Introducing a charge on the substituents leads to substantial and characteristic changes in the individual hydrogen bond lengths when compared to the neutral AT pair. However, the trends along the series of negative, neutral, and positive substituents are less systematic and less pronounced than for GC. In certain instances, internal proton transfer from thymine to adenine occurs. Our results suggest that AT is a less suitable candidate than GC in the quest for chemically controlled nanoswitches.     

7‐Iodo‐5‐aza‐7‐deazaguanine ribonucleoside: crystal structure,physical properties,base‐pair stability and functionalization

The positional change of nitrogen‐7 of the RNA constituent guanosine to the bridgehead position‐5 leads to the base‐modified nucleoside 5‐aza‐7‐deazaguanosine. Contrary to guanosine, this molecule cannot form Hoogsteen base pairs and the Watson–Crick proton donor site N3—H becomes a proton‐acceptor site. This causes changes in nucleobase recognition in nucleic acids and has been used to construct stable `all‐purine' DNA and DNA with silver‐mediated base pairs. The present work reports the single‐crystal X‐ray structure of 7‐iodo‐5‐aza‐7‐deazaguanosine, C<sub>10</sub>H<sub>12</sub>IN<sub>5</sub>O<sub>5</sub> ( 1 ). The iodinated nucleoside shows an anti conformation at the glycosylic bond and an N conformation (O4′‐endo) for the ribose moiety, with an antiperiplanar orientation of the 5′‐hydroxy group. Crystal packing is controlled by interactions between nucleobase and sugar moieties. The 7‐iodo substituent forms a contact to oxygen‐2′ of the ribose moiety. Self‐pairing of the nucleobases does not take place. A Hirshfeld surface analysis of 1 highlights the contacts of the nucleobase and sugar moiety (O—H…O and N—H…O). The concept of pK‐value differences to evaluate base‐pair stability was applied to purine–purine base pairing and stable base pairs were predicted for the construction of `all‐purine' RNA. Furthermore, the 7‐iodo substituent of 1 was functionalized with benzofuran to detect motional constraints by fluorescence spectroscopy.     

A Pyrimidopyrimidine Janus‐AT Nucleoside with Improved Base‐Pairing Properties to both A and T within a DNA Duplex: The Stabilizing Effect of a Second Endocyclic Ring Nitrogen

Janus bases are heterocyclic nucleic acid base analogs that present two different faces able to simultaneously hydrogen bond to nucleosides that form Watson–Crick base pairs. The synthesis of a Janus‐AT nucleotide analogue, ^N J_AT , that has an additional endocyclic ring nitrogen and is thus more capable of efficiently discriminating T/A over G/C bases when base‐pairing in a standard duplex‐DNA context is described. Conversion to a phosphoramidite ultimately afforded incorporation into an oligonucleotide. In contrast to the first generation of carbocyclic Janus heterocycles, it remains in its unprotonated state at physiological pH and, therefore, forms very stable Watson–Crick base pairs with either A or T bases. Biophysical and computational methods indicate that ^N J_AT is an improved candidate for sequence‐specific genome targeting.     

Mismatch base pairing of the mutagen 8‐oxoguanine and its derivatives with adenine: A theoretical search for possible antimutagenic agents

Molecular geometries of 8‐oxoguanine (8OG), those of its substituted derivatives with the substitutions CH₂, CF₂, CO, CNH, O, and S in place of the N7H7 group, adenine (A), and the base pairs of 8OG and its substituted derivatives with adenine were optimized using the RHF/6‐31+G* and B3LYP/6‐31+G* methods in gas phase. All the molecules and their hydrogen‐bonded complexes were solvated in aqueous media employing the polarized continuum model (PCM) of the self‐consistent reaction field (SCRF) theory using the RHF/6‐31+G* and B3LYP/6‐31+G* methods. The optimized geometrical parameters of the 8OG‐A base pair at the RHF/6‐31+G* and B3LYP/6‐31+G* levels of theory agree satisfactorily with those of an oligonucleotide containing the base pair found from X‐ray crystallography. The pattern of hydrogen bonding in the CF₂‐ and O‐substituted 8OG‐A base pair is of Watson–Crick type and that in the unsubstituted and CH₂‐, CNH‐, and S‐substituted base pairs is of Hoogsteen type. In the CO‐substituted base pair, the hydrogen bonding pattern is of neither Watson–Crick nor Hoogsteen type. The CF₂‐substitution appears to introduce steric hindrance for stacking of DNA bases. On the basis of these results, it appears that among all the substituted 8OG molecules considered here, the O‐substituted derivative may be useful as an antimutagenic drug. It is, however, subject to experimental verification. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Unexpected A·T(WC)↔A·T(rWC)/A·T(rH) and A·T(H)↔A·T(rH)/A·T(rWC) conformational transitions between the classical A·T DNA base pairs: A QM/QTAIM comprehensive study

In this study, using QM/QTAIM calculations in the continuum with ε = 1 under normal conditions, we have revealed for the first time the nondissociative A·T(WC)↔A·T(rWC)/A·T(rH) and A·T(H)↔A·T(rH)/A·T(rWC) conformational transitions. It was established that they proceed via the essentially nonplanar transition states (С₁ symmetry) through the intermediates, which are wobbled conformers (С₁ symmetry) theoretically predicted in our previous work (Brovarets’ et al., Frontiers in Chemistry, 2018, 6:8, 10.3389/fchem.2018.00008) of the classical А·Т DNA base pairs—Watson–Crick А·Т(WC), reverse Watson–Crick А·Т(rWC), Hoogsteen А·Т(Н) and reverse Hoogsteen А·Т(rН). At this, the A·T(H)↔A·T(rWC) and A·T(WC)↔A·T(rH) conformational transformations are controlled by the transition states (TSs) stabilized by the participation of the intermolecular (T)N3H···N6(A) H‐bond (∼3.70 kcal·mol⁻¹) between the imino group N3H of T and pyramidilized amino group N6H₂ of A. Gibbs free energies of activation for these processes consist 12.22 and 11.11 kcal·mol⁻¹, accordingly, under normal conditions. TSs, which control the A·T(WC)↔A·T(rWC) and A·T(H)↔A·T(rH) conformational transitions are stabilized by the participation of the intermolecular (T)N3H···N6(A) H‐bond (5.82 kcal·mol⁻¹) and bifurcating intermolecular (T)N3H···N6(A) (5.00) and (T)N3H···N7(A) (0.61 kcal·mol⁻¹) H‐bonds, accordingly. Notably, in these two TSs amino group N6H₂ of A is significantly pyramidilized; Gibbs free energies of activation for these reactions are 19.07 and 19.71 kcal·mol⁻¹, accordingly.     

Covalently Cross-Linked Watson–Crick Base Pair Models

Structural characteristics of Watson–Crick hydrogen-bonded base pairs are displayed by methylene-bridged base pairs of type A . The shown superposition of the X-ray structure obtained for the base pair A (Rib¹=Et; Rib²=Me) over that of a C–G base pair illustrates that A occupies an area similar to that occupied by a traditional Watson–Crick hydrogen-bonded base pair. Temperature-dependent ¹H NMR studies indicate that the energy barrier for rotation along its CH₂ bridge is about 10 kcal mol⁻¹, and that it exists predominantly in one conformer at −70°C.     

Comparative studies between hydrated hydrogen bonded and stacked DNA base pair

Influence of hydration on the Watson–Crick guanine–cytosine hydrogen bonded (h-bonded) base pair (GC) and stacked pair (G/C) was investigated in their first hydration shell. An electrostatic based approach has been used to identify the potential binding sites for water molecules around GC and G/C pairs. Several geometries of the complexes, GC…(H₂O)_n and G/C…(H₂O)_n (n=1–6) were investigated using HF/6-31G** and HF/6-31G++** methods. Further minimization calculations were performed at both B3P86/6-31G** and MP2/6-31G** levels to assess the role of electron correlation contribution in the hydration process. It can be concluded from the present findings that the stacked base-pair hydrate better than the corresponding h-bonded base pair, and DNA base pairs can accommodate up to 4–5 water molecules whereas stacked pair do accommodate 5–6 water molecules.     

Preopening of the DNA base pairs

The lower‐energy stable structures of the A?T base pair are revealed under a search of its potential energy surface in the vicinity of its Watson–Crick configuration performed at the PM3 computational level. Their properties and the mutual position of the nucleic acid bases A and T in these structures allow to partition them into three classes: partially preopened, stretched, and fully preopened. The preferable monohydration sites of the preopened, stretched, and fully preopened pairs are also determined. It is demonstrated, first, that the monohydration of the A?T pair at particular sites favors a base pair preopeness and, second, that a binding of the water molecule to the preopened A?T base pair on the major groove side enhances its stabilization. It is also shown that water molecule placing in the vicinity of the central H bond of the A?T pair significantly facilitates its preopening. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 82: 193–204, 2001     

Computational investigation of thermochemical properties of non-natural C-nucloebases: different hydrogen-bonding preferences for non-natural Watson–Crick base pairs

In the present density functional theory study, we have compared intrinsic properties of non-natural nucleobases (acA, acG, acC, and acT nucleobases) such as proton affinities, gas phase acidities, tautomerization, and hydrogen-bonding properties with those in normal Watson–Crick nucleobases (A, G, C, T nucleobases). The hydrogen-bonding interactions in non-natural and Watson–Crick base pairs were studied at B3LYP/6-311++G (d,p) level regarding their geometries, energies, and topological features of the electron density. The quantum theory of atoms-in-molecule (QTAIM) and natural bond orbital (NBO) analyses were employed to elucidate the interaction characteristics in base pairs. The electron density ρ(r) as well as its Laplacian $ \nabla^{2} $ ρ(r) at the hydrogen bond critical point predicted by QTAIM is strongly correlated with hydrogen bond structural parameter and the second-order perturbation energies in NBO scheme. Our results show that most of hydrogen bonds in normal Watson–Crick and non-natural base pairs must be considered as electrostatic interactions. Results of calculations revealed that energetic values of hydrogen bonds in T–A base pair are more than those in ac T–ac A base pair, while values of hydrogen bonds in C–G base pair and ac C–ac G base pair are almost the same. These results confirmed stability order of stabilization energies of these base pairs.     

Pairing of Isolated Nucleobases: Double Resonance Laser Spectroscopy of Adenine–Thymine

The vibronic spectrum of the adenine–thymine (A–T) base pair was obtained by one‐color resonant two‐photon ionization (R2PI) spectroscopy in a free jet of thermally evaporated A and T under conditions favorable for formation of small clusters. The onset of the spectrum at 35 064 cm^?1 exhibits a large red shift relative to the π–π* origin of 9H‐adenine at 36 105 cm^?1. The IR–UV spectrum was assigned to cluster structures with HNH???O?C/N???HN hydrogen bonding by comparison with the IR spectra of A and T monomers and with ab initio calculated vibrational spectra of the most stable A–T isomers. The Watson–Crick A–T base pair is not the most stable base‐pair structure at different levels of ab initio theory, and its vibrational spectrum is not in agreement with the observed experimental spectrum. Experiments with methylated A and T were performed to further support the structural assignment.     

3‐Cyano‐6‐hydroxy‐4‐methyl‐2‐pyridone: two new pseudopolymorphs and two cocrystals with products of an in situ nucleophilic aromatic substitution

Four crystal structures of 3‐cyano‐6‐hydroxy‐4‐methyl‐2‐pyridone (CMP), viz. the dimethyl sulfoxide monosolvate, C₇H₆N₂O₂·C₂H₆OS, (1), the N,N‐dimethylacetamide monosolvate, C₇H₆N₂O₂·C₄H₉NO, (2), a cocrystal with 2‐amino‐4‐dimethylamino‐6‐methylpyrimidine (as the salt 2‐amino‐4‐dimethylamino‐6‐methylpyrimidin‐1‐ium 5‐cyano‐4‐methyl‐6‐oxo‐1,6‐dihydropyridin‐2‐olate), C₇H₁₃N₄⁺·C₇H₅N₂O₂⁻, (3), and a cocrystal with N,N‐dimethylacetamide and 4,6‐diamino‐2‐dimethylamino‐1,3,5‐triazine [as the solvated salt 2,6‐diamino‐4‐dimethylamino‐1,3,5‐triazin‐1‐ium 5‐cyano‐4‐methyl‐6‐oxo‐1,6‐dihydropyridin‐2‐olate–N,N‐dimethylacetamide (1/1)], C₅H₁₁N₆⁺·C₇H₅N₂O₂⁻·C₄H₉NO, (4), are reported. Solvates (1) and (2) both contain the hydroxy group in a para position with respect to the cyano group of CMP, acting as a hydrogen‐bond donor and leading to rather similar packing motifs. In cocrystals (3) and (4), hydrolysis of the solvent molecules occurs and an in situ nucleophilic aromatic substitution of a Cl atom with a dimethylamino group has taken place. Within all four structures, an R₂²(8) N—H...O hydrogen‐bonding pattern is observed, connecting the CMP molecules, but the pattern differs depending on which O atom participates in the motif, either the ortho or para O atom with respect to the cyano group. Solvents and coformers are attached to these arrangements via single‐point O—H...O interactions in (1) and (2) or by additional R₄⁴(16) hydrogen‐bonding patterns in (3) and (4). Since the in situ nucleophilic aromatic substitution of the coformers occurs, the possible Watson–Crick C–G base‐pair‐like arrangement is inhibited, yet the cyano group of the CMP molecules participates in hydrogen bonds with their coformers, influencing the crystal packing to form chains.     

The surprising pairing of 2‐aminoimidazo[1,2‐a][1,3,5]triazin‐4‐one,a component of an expanded DNA alphabet

Synthetic biologists demonstrate their command over natural biology by reproducing the behaviors of natural living systems on synthetic biomolecular platforms. For nucleic acids, this is being done stepwise, first by adding replicable nucleotides to DNA, and then removing its standard nucleotides. This challenge has been met in vitro with `six‐letter' DNA and RNA, where the Watson–Crick pairing `concept' is recruited to increase the number of independently replicable nucleotides from four to six. The two nucleobases most successfully added so far are Z and P , which present a donor–donor–acceptor and an acceptor–acceptor–donor pattern, respectively. This pair of nucleobases are part of an `artificially expanded genetic information system' (AEGIS). The Z nucleobase has been already crystallized, characterized, and published in this journal [Matsuura et al. (2016). Acta Cryst. C 72 , 952–959]. More recently, variants of Taq polymerase have been crystallized with the pair P : Z trapped in the active site. Here we report the crystal structure of the nucleobase 2‐aminoimidazo[1,2‐a][1,3,5]triazin‐4‐one (trivially named P ) as the monohydrate, C₅H₅N₅O·H₂O. The nucleobase P was crystallized from water and characterized by X‐ray diffraction. Interestingly, the crystal structure shows two tautomers of P packed in a Watson–Crick fashion that cocrystallized in a 1:1 ratio.     

Nucleotide–amino acid interactions in the l‐His–IMP·MeOH·H2O complex

In the crystal structure of the methanol‐solvated monohydrated complex of l ‐histidine (His) with inosine 5′‐monophosphate (IMP), namely l ‐histidinium inosine‐5′‐phosphate methanol solvate monohydrate, C₆H₁₀N₃O₂⁺·C₁₀H₁₂N₄O₈P⁻·CH₃OH·H₂O, most of the interactions between IMP anions (anti/C3′‐endo/gauche–gauche conformers) are realized between the riboses and hypoxanthine bases in a trans sugar‐edge/sugar‐edge geometry, and between the phosphate groups. The base Watson–Crick edge is involved in additional methanol‐mediated IMP...MeOH...IMP contacts. Specific and nonspecific nucleotide–amino acid (IMP...His) interactions engage the Hoogsteen edges of the base and phosphate group, respectively. Additional stabilization of His...IMP contacts is provided by π–π stacking between the imidazolium ring of His and the hypoxanthine base of IMP. The results may indicate the possible recognition mechanism between His and IMP.     

A Reversible Proton Relay Process Mediated by Hydrogen‐Bonding Interactions in [FeFe]Hydrogenase Modeling

A reversible and temperature‐dependent proton‐relay process is demonstrated for a Fe₂ complex possessing a terminal thiolate in the presence of nitrogen‐based acids. The terminal sulfur site (S^t) of the complex forms a hydrogen‐bond interaction with N,N‐dimethylanilinium acid at 183 K. The Fe₂ core, instead, is protonated to generate a bridging hydride at 298 K. Reversibility is observed for the tautomerization between the hydrogen‐bonded pair and the Fe–hydride species. X‐ray structural analysis of the hydrogen‐bonded species at 193 K reveals a short N(H)???S^t contact. Employment of pyridinium acid also results in similar behavior, with reversible proton–hydride interconversion. DFT investigation of the proton‐transfer pathways indicates that the pK_a value of the hydrogen‐bonded species is enhanced by 3.2 pK_a units when the temperature is decreased from 298 K to 183 K.     

Cocrystals of 1,4‐diethynylbenzene with 1,3‐diacetylbenzene and benzene‐1,4‐dicarbaldehyde exhibiting strong nonconventional alkyne–carbonyl C—H…O hydrogen bonds between the components

Weak interactions between organic molecules are important in solid‐state structures where the sum of the weaker interactions support the overall three‐dimensional crystal structure. The sp‐C—H…N hydrogen‐bonding interaction is strong enough to promote the deliberate cocrystallization of a series of diynes with a series of dipyridines. It is also possible that a similar series of cocrystals could be formed between molecules containing a terminal alkyne and molecules which contain carbonyl O atoms as the potential hydrogen‐bond acceptor. I now report the crystal structure of two cocrystals that support this hypothesis. The 1:1 cocrystal of 1,4‐diethynylbenzene with 1,3‐diacetylbenzene, C₁₀H₆·C₁₀H₁₀O₂, (1), and the 1:1 cocrystal of 1,4‐diethynylbenzene with benzene‐1,4‐dicarbaldehyde, C₁₀H₆·C₈H₆O₂, (2), are presented. In both cocrystals, a strong nonconventional ethynyl–carbonyl sp‐C—H…O hydrogen bond is observed between the components. In cocrystal (1), the C—H…O hydrogen‐bond angle is 171.8 (16)° and the H…O and C…O hydrogen‐bond distances are 2.200 (19) and 3.139 (2) Å, respectively. In cocrystal (2), the C—H…O hydrogen‐bond angle is 172.5 (16)° and the H…O and C…O hydrogen‐bond distances are 2.25 (2) and 3.203 (2) Å, respectively.     

Aqua[bis(pyrimidin‐2‐yl‐κN)amine](carbonato‐κ2O,O′)copper(II) dihydrate

The title mononuclear complex, [Cu(CO₃)(C₈H₇N₅)(H₂O)]·2H₂O, was obtained by fixation of CO₂ by a mixture of copper(II) tetra­fluoro­borate and the ligand bis­(pyrimidin‐2‐yl)­amine in ethanol/water. The Cu^II ion of the complex has a distorted square‐pyramidal environment, with a basal plane formed by two N atoms of the ligand and two chelating O atoms of the carbonate group, while the apical position is occupied by the O atom of the coordinating water mol­ecule. In the solid state, hydrogen‐bonding interactions are dominant, the most unusual being the Watson–Crick‐type coplanar ligand pairing through two N—H?N bonds. Lattice water mol­ecules also participate in hydrogen bonding.     

The tropolone–isobutylamine complex: a hydrogen‐bonded troponoid without dominant π–π interactions

Tropolone long has served as a model system for unraveling the ubiquitous phenomena of proton transfer and hydrogen bonding. This molecule, which juxtaposes ketonic, hydroxylic, and aromatic functionalities in a framework of minimal complexity, also has provided a versatile platform for investigating the synergism among competing intermolecular forces, including those generated by hydrogen bonding and aryl coupling. Small members of the troponoid family typically produce crystals that are stabilized strongly by pervasive π–π, C—H…π, or ion–π interactions. The organic salt (TrOH·iBA) formed by a facile proton‐transfer reaction between tropolone (TrOH) and isobutylamine (iBA), namely isobutylammonium 7‐oxocyclohepta‐1,3,5‐trien‐1‐olate, C₄H₁₂N⁺·C₇H₅O₂⁻, has been investigated by X‐ray crystallography, with complementary quantum‐chemical and statistical‐database analyses serving to elucidate the nature of attendant intermolecular interactions and their synergistic effects upon lattice‐packing phenomena. The crystal structure deduced from low‐temperature diffraction measurements displays extensive hydrogen‐bonding networks, yet shows little evidence of the aryl forces (viz. π–π, C—H…π, and ion–π interactions) that typically dominate this class of compounds. Density functional calculations performed with and without the imposition of periodic boundary conditions (the latter entailing isolated subunits) documented the specificity and directionality of noncovalent interactions occurring between the proton‐donating and proton‐accepting sites of TrOH and iBA, as well as the absence of aromatic coupling mediated by the seven‐membered ring of TrOH. A statistical comparison of the structural parameters extracted for key hydrogen‐bond linkages to those reported for 44 previously known crystals that support similar binding motifs revealed TrOH·iBA to possess the shortest donor–acceptor distances of any troponoid‐based complex, combined with unambiguous signatures of enhanced proton‐delocalization processes that putatively stabilize the corresponding crystalline lattice and facilitate its surprisingly rapid formation under ambient conditions.     

Cocrystals of 6‐methyl‐2‐thiouracil: presence of the acceptor–donor–acceptor/donor–acceptor–donor synthon

The results of seven cocrystallization experiments of the antithyroid drug 6‐methyl‐2‐thiouracil (MTU), C₅H₆N₂OS, with 2,4‐diaminopyrimidine, 2,4,6‐triaminopyrimidine and 6‐amino‐3H‐isocytosine (viz. 2,6‐diamino‐3H‐pyrimidin‐4‐one) are reported. MTU features an ADA (A = acceptor and D = donor) hydrogen‐bonding site, while the three coformers show complementary DAD hydrogen‐bonding sites and therefore should be capable of forming an ADA/DAD N—H...O/N—H...N/N—H...S synthon with MTU. The experiments yielded one cocrystal and six cocrystal solvates, namely 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine–1‐methylpyrrolidin‐2‐one (1/1/2), C₅H₆N₂OS·C₄H₆N₄·2C₅H₉NO, (I), 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine (1/1), C₅H₆N₂OS·C₄H₆N₄, (II), 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine–N,N‐dimethylacetamide (2/1/2), 2C₅H₆N₂OS·C₄H₆N₄·2C₄H₉NO, (III), 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine–N,N‐dimethylformamide (2/1/2), C₅H₆N₂OS·0.5C₄H₆N₄·C₃H₇NO, (IV), 2,4,6‐triaminopyrimidinium 6‐methyl‐2‐thiouracilate–6‐methyl‐2‐thiouracil–N,N‐dimethylformamide (1/1/2), C₄H₈N₅⁺·C₅H₅N₂OS⁻·C₅H₆N₂OS·2C₃H₇NO, (V), 6‐methyl‐2‐thiouracil–6‐amino‐3H‐isocytosine–N,N‐dimethylformamide (1/1/1), C₅H₆N₂OS·C₄H₆N₄O·C₃H₇NO, (VI), and 6‐methyl‐2‐thiouracil–6‐amino‐3H‐isocytosine–dimethyl sulfoxide (1/1/1), C₅H₆N₂OS·C₄H₆N₄O·C₂H₆OS, (VII). Whereas in cocrystal (I) an R₂²(8) interaction similar to the Watson–Crick adenine/uracil base pair is formed and a two‐dimensional hydrogen‐bonding network is observed, the cocrystals (II)–(VII) contain the triply hydrogen‐bonded ADA/DAD N—H...O/N—H...N/N—H...S synthon and show a one‐dimensional hydrogen‐bonding network. Although 2,4‐diaminopyrimidine possesses only one DAD hydrogen‐bonding site, it is, due to orientational disorder, triply connected to two MTU molecules in (III) and (IV).     

Pyrrolo‐dC Metal‐Mediated Base Pairs in the Reverse Watson–Crick Double Helix: Enhanced Stability of Parallel DNA and Impact of 6‐Pyridinyl Residues on Fluorescence and Silver‐Ion Binding

Reverse Watson–Crick DNA with parallel‐strand orientation (ps DNA) has been constructed. Pyrrolo‐dC (PyrdC) nucleosides with phenyl and pyridinyl residues linked to the 6 position of the pyrrolo[2,3‐d]pyrimidine base have been incorporated in 12‐ and 25‐mer oligonucleotide duplexes and utilized as silver‐ion binding sites. Thermal‐stability studies on the parallel DNA strands demonstrated extremely strong silver‐ion binding and strongly enhanced duplex stability. Stoichiometric UV and fluorescence titration experiments verified that a single ^2pyPyrdC–^2pyPyrdC pair captures two silver ions in ps DNA. A structure for the PyrdC silver‐ion base pair that aligns 7‐deazapurine bases head‐to‐tail instead of head‐to‐head, as suggested for canonical DNA, is proposed. The silver DNA double helix represents the first example of a ps DNA structure built up of bidentate and tridentate reverse Watson–Crick base pairs stabilized by a dinuclear silver‐mediated PyrdC pair.