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     

Quantum chemical study of the hydrogen‐bonded patterns in A · T base pair of DNA: Origins of tautomeric mispairs,base flipping,and Watson–Crick ⇒ Hoogsteen conversion

The current work aims to thoroughly investigate a variety of facets of the hydrogen‐bond pattern of the Watson–Crick A · T base pair of DNA. It offers a novel mechanism of the origin of the hydrogen‐bonded mispairing in the A · T base pair based on the analysis of the lower‐energy portion of the total potential energy surface of all possible rearrangements of the hydrogen‐bond patterns in this pair, performed at the Hartree–Fock (HF), second‐order Moller–Plesset (MP2)//HF, and B3LYP computational levels in conjunction with 6‐31+G(d) basis set. The specific novelty of this mechanism is that the primary step consists of a single proton transfer along the N₃(T)–H … N₁ (A) hydrogen bond, thus leading to a transition state that is not directly related to the proton transfer. Rather, it governs the interbase shift within the A · T pair switching the hydrogen‐bonded pattern and then separating the normal A · T pair from the mispairing valley on its potential energy surface. The latter comprises three mismatched base pairs, easily converted to each other because of lower barriers (≈1 kcal/mol) of the corresponding proton transfers. It is demonstrated that, in terms of the Gibbs free energy taken at room T = 298.15 K, the most stable mispair in such valley is predicted to be less stable by 9.7 ± 2 kcal/mol than the Watson–Crick pair, thus implying that the spontaneous point mutations of this type occur as infrequently as to be characterized by an equilibrium constant of 10^?6 to 10^?9. This estimate falls into the well‐known experimental range of mutation frequency per base pair. The structure of a so‐called “base flipping” of the A · T base pair, originated from a breaking of its N₃(T)‐H … N₁ (A) hydrogen bond, is also found and reported in the current work for the first time. The transition state A · T ${}_{\text{ts}}^{\text{WC?H}}$ , which governs the conversion of the Watson–Crick pair of adenine · thymine into the Hoogsteen one and is related to a breaking of the N₆(A)–H … O₄(T), is also obtained and its energetical and geometrical features are discussed. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003     

Contiguous metal-mediated base pairs comprising two Ag(I) ions

The incorporation of transition‐metal ions into nucleic acids by using metal‐mediated base pairs has proved to be a promising strategy for the site‐specific functionalization of these biomolecules. We report herein the formation of Ag⁺‐mediated Hoogsteen‐type base pairs comprising 1,3‐dideaza‐2′‐deoxyadenosine and thymidine. By defunctionalizing the Watson–Crick edge of adenine, the formation of regular base pairs is prohibited. The additional substitution of the N3 nitrogen atom of adenine by a methine moiety increases the basicity of the exocyclic amino group. Hence, 1,3‐dideazaadenine and thymine are able to incorporate two Ag⁺ ions into their Hoogsteen‐type base pair (as compared with one Ag⁺ ion in base pairs with 1‐deazaadenine and thymine). We show by using a combination of experimental techniques (UV and circular dichroism (CD) spectroscopies, dynamic light scattering, and mass spectrometry) that this type of base pair is compatible with different sequence contexts and can be used contiguously in DNA double helices. The most stable duplexes were observed when using a sequence containing alternating purine and pyrimidine nucleosides. Dispersion‐corrected density functional theory calculations have been performed to provide insight into the structure, formation and stabilization of the twofold metalated base pair. They revealed that the metal ions within a base pair are separated by an Ag???Ag distance of about 2.88 Å. The Ag–Ag interaction contributes some 16 kcal mol^?1 to the overall stability of the doubly metal‐mediated base pair, with the dominant contribution to the Ag–Ag bonding resulting from a donor–acceptor interaction between silver 4d‐type and 4s orbitals. These Hoogsteen‐type base pairs enable a higher functionalization of nucleic acids with metal ions than previously reported metal‐mediated base pairs, thereby increasing the potential of DNA‐based nanotechnology.     

The Protonated Guanine–Cytosine Base Pair

Protonated base pairs were recently implicated in the context of DNA proton transfer and charge migration. The effects of protonating different sites of the guanine–cytosine (GC) base pair are studied here by using the DZP++ B3LYP density functional method. Optimized structures for the protonated GC base pair are compared with those of parent GC and the neutral hydrogenated GC radical (GCH). Proton and hydrogen‐atom additions significantly disturb the structure of the GC base pair. However, the structural perturbations arising from protonation are often less than those arising from hydrogenation of GC. Protonation of the GC base pair causes significant strengthening of the interstrand hydrogen bonds and a concomitant increase in the base dissociation energies. The adiabatic ionization potentials (AIPs), vertical ionization potentials (VIPs), and proton affinities (PAs) for the different protonation sites of the GC base pair are predicted. The N7 site of guanine is the preferred site for protonation of the GC base pair.     

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.     

Interaction of angelicin with DNA‐bases (III) DFT and ab initio second‐order Moeller–Plesset study

Angelicin geometry was optimized at MP2/6‐31+G(d,p) level and compared with X‐ray experimental data. The highest π‐electron density was found to be localized on C1? C2 and on C13? C14 as confirmed by the calculated bond length and bond order values. Spectrophptometric properties of angelicin were measured and compared with the computed within the TD‐DFT. Quantum chemical methods were used to study the interaction of angelicin, as a nonlinear furocoumarin, with DNA bases and base pairs. The interactions with DNA bases and base pairs were studied to shade more light on the nature of the intercalation binding forces between angelicin and DNA. Comparing computed electronic properties of angelicin with that of linear psoralens show that the former is a weaker intercalator. The geometry of complexes of angelicin with adenine, thymine, adenine–thymine base pair, cytocine, guanine as well as cytocine–guanine base pair have been optimized in two main orientations, planar and stacked, at the levels of B3LYP/cc‐pVDZ, MP2/6‐31G(d,p) and MP2/cc‐pVDZ. Effect of vertical distance and rotational angle between the stacked molecules on the interaction energy were investigated by the aforementioned methods in gas phase and water media. It was found that ab initio methods which account for the electron correlation effects are the minimum level for studying the noncovalent interactions. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

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.     

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.     

Supramolecular porphyrin assemblies through amidinium-carboxylate salt bridges and fast intra-ensemble excited energy transfer

Well‐defined supramolecular assemblies of Zn and free‐base porphyrins are constructed through the formation of amidinium–carboxylate salt bridges. A one‐to‐one donor–acceptor pair and a four‐to‐one antenna‐type assembly are investigated. The steady‐state and time‐resolved fluorescence measurements unequivocally showed that efficient singlet–singlet excited energy transfer from the Zn–porphyrin complex to the free‐base porphyrin takes place in these assemblies. Indeed, the observed energy‐transfer rates in both types of assemblies are much faster than those the Förster mechanism would suggest, implying the involvement of an intermolecular through‐bond mechanism.     

A computational study of base‐catalyzed reactions between isocyanates and epoxides affording 2‐oxazolidones and isocyanurates

Title reactions were investigated with ab initio calculations. Methyl isocyanate and ethylene oxide were adopted as model reactants. The products, 2‐oxazolidones and isocyanurates, cannot be yielded without a base catalyst. The 2‐oxazolidone may be produced by a dual S_N2 reaction, where the catalyst base (e.g., Cl⁻) is a nucleophile and a leaving group on the ethylene–oxide carbon. Isocyanurate is generated by the stepwise association of three isocyanate molecules, where one of the molecules is initially linked with a base. The six‐membered ring isocyanurate is isomerized stepwise into the components isocyanate and 2‐oxazolidone. A tetrahedral type of complex between the isocyanurate and a base‐catalyzed ethylene oxide is the key intermediate for the isomerization. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 316–326, 2001     

Theoretical Investigation of the Coupling between Hydrogen‐Atom Transfer and Stacking Interaction in Adenine–Thymine Dimers

Three different dimers of the adenine–thymine (A‐T) base pair are studied to point out the changes of important properties (structure, atomic charge, energy and so on) induced by coupling between the movement of the atoms in the hydrogen bonds and the stacking interaction. The comparison of these results with those for the A‐T monomer system explains the role of the stacking interaction in the hydrogen‐atom transfer in this biologically important base pair. The results support the idea that this coupling depends on the exact dimer considered and is different for the N? N and N? O hydrogen bonds. In particular, the correlation between the hydrogen transfer and the stacking interaction is more relevant for the N? N bridge than for the N? O one. Also, the two different mechanisms of two‐hydrogen transfer (step by step and concerted) can be modified by the stacking interaction between the base pairs.     

Quadracyclic Adenine: A Non‐Perturbing Fluorescent Adenine Analogue

Fluorescent‐base analogues (FBAs) comprise a group of increasingly important molecules for the investigation of nucleic acid structure and dynamics as well as of interactions between nucleic acids and other molecules. Here, we report on the synthesis, detailed spectroscopic characterisation and base‐pairing properties of a new environment‐sensitive fluorescent adenine analogue, quadracyclic adenine (qA). After developing an efficient route of synthesis for the phosphoramidite of qA it was incorporated into DNA in high yield by using standard solid‐phase synthesis procedures. In DNA qA serves as an adenine analogue that preserves the B‐form and, in contrast to most currently available FBAs, maintains or even increases the stability of the duplex. We demonstrate that, unlike fluorescent adenine analogues, such as the most commonly used one, 2‐aminopurine, and the recently developed triazole adenine, qA shows highly specific base‐pairing with thymine. Moreover, qA has an absorption band outside the absorption of the natural nucleobases (>300 nm) and can thus be selectively excited. Upon excitation the qA monomer displays a fluorescence quantum yield of 6.8 % with an emission maximum at 456 nm. More importantly, upon incorporation into DNA the fluorescence of qA is significantly less quenched than most FBAs. This results in quantum yields that in some sequences reach values that are up to fourfold higher than maximum values reported for 2‐aminopurine. To facilitate future utilisation of qA in biochemical and biophysical studies we investigated its fluorescence properties in greater detail and resolved its absorption band outside the DNA absorption region into distinct transition dipole moments. In conclusion, the unique combination of properties of qA make it a promising alternative to current fluorescent adenine analogues for future detailed studies of nucleic acid‐containing systems.     

Molecular Switching Behavior in Isosteric DNA Base Pairs

The structures and proton‐coupled behavior of adenine–thymine (A‐T) and a modified base pair containing a thymine isostere, adenine–difluorotoluene (A‐F), are studied in different solvents by dispersion‐corrected density functional theory. The stability of the canonical Watson–Crick base pair and the mismatched pair in various solvents with low and high dielectric constants is analyzed. It is demonstrated that A‐F base pairing is favored in solvents with low dielectric constant. The stabilization and conformational changes induced by protonation are also analyzed for the natural as well as the mismatched base pair. DNA sequences capable of changing their sequence conformation on protonation are used in the construction of pH‐based molecular switches. An acidic medium has a profound influence in stabilizing the isostere base pair. Such a large gain in stability on protonation leads to an interesting pH‐controlled molecular switch, which can be incorporated in a natural DNA tract.     

Multicanonical Monte Carlo calculation of the free‐energy map of the base–amino acid interaction

The specific interactions between base pairs and amino acids were studied by the multicanonical Monte Carlo method. We sampled numerous interaction configurations and side‐chain conformations of the amino acid by the multicanonical algorithm, and calculated the free energies of the interactions between an amino acid at given C_α positions and a fixed base pair. The contour maps of free energy derived from this calculation represent the preferred C_α position of the amino acid around the base, and these maps of various combinations of bases and amino acids can be used to quantify the specificity of intrinsic base–amino acid interactions. Similarly, enthalpy and entropy maps will provide further details of the specific interactions. We have also calculated the free‐energy map of the orientations of the C_α C_β bond vector, which indicates the preferential orientation of the amino acid against the base. We compared the results obtained by the multicanonical method with those of the exhaustive sampling and canonical Monte Carlo methods. The free‐energy map of the base–amino acid interaction obtained by the multicanonical simulation method was nearly identical to the accurate result derived from the exhaustive sampling method. This indicates that a single multicanonical Monte Carlo simulation can produce an accurate free‐energy map. Multicanonical Monte Carlo sampling produced free‐energy maps that were more accurate than those produced by canonical Monte Carlo sampling. Thus, the multicanonical Monte Carlo method can serve as a powerful tool for estimating the free‐energy landscape of base–amino acid interactions and for elucidating the mechanism by which amino acids of proteins recognize particular DNA base pairs. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 954–962, 2000     

Structures and energetics of the deprotonated adenine-uracil base pair, including proton-transferred systems

The B3LYP/DZP++ level of theory has been employed to investigate the structures and energetics of the deprotonated adenine-uracil base pairs, (AU-H)-. Formation of the lowest-energy structure, [A(N9)-U]- (which corresponds to deprotonation at the N9 atom of adenine), through electron attachment to the corresponding neutral is accompanied by proton transfer from the uracil N3 atom to the adenine N1 atom. The driving force for this proton transfer is a significant stabilization from the base pairing in the proton transferred form. Such proton transfer upon electron attachment is also observed for the [A(N6b)-U]- and [A(C2)-U]- anions. Electron attachment to the A-U(N3) radical causes strong lone pair repulsion between the adenine N1 and the uracil N3 atoms, driving the two bases apart. Similarly, lone pair repulsion in the anion A(N6a)-U causes the loss of coplanarity of the two base units. The computed adiabatic electron attachment energies for nine AU-H radicals range from 1.86 to 3.75 eV, implying that the corresponding (AU-H)- anions are strongly bound. Because of the large AEAs of the (AU-H) radicals, the C-H and N-H bond dissociation in the AU- base pair anions requires less energy than the neutral AU base pair. The computed C-H and N-H bond dissociation energies for the AU- anion (i.e., the AU base pair plus one electron) are in the range 1.0-3.2 eV, while those for neutral AU are 4.08 eV or higher.     

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.     

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.     

Water‐soluble cationic polypyrrole based probe for fluorometric and voltammetric detection of base pair mismatched oligonucleotides

Water‐soluble cationic polypyrrole, poly(N‐(4‐butyl‐(1‐methylimidazole)) pyrrole bromide) (PNBMIP‐Br), was synthesized and applied for base pair mismatched oligonucleotides detection. Interactions between PNBMIP‐Br and a series of oligonucleotides, including ss‐DNA and base pair mismatched ds‐DNA were studied by fluorometric spectra, circular dichroism spectra and voltammetric detection. The results showed that the electrostatic attraction and fluorescence resonance energy transfer of PNBMIP‐Br/DNA complexes resulted in an amplification and effective recognition of the fluorescence signals. The results of cyclic voltammograms indicate that voltammetric detection is an effective method to distinguish ss‐DNA and ds‐DNA. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1600–1605     

Sequence, structure and energy transfer in DNA

Excitation energy transfer in DNA has similarities to charge transfer, but the transport is of an excited state, not of mass or charge. Use of the fluorescent, modified adenine base 2‐aminopurine (2AP) as an energy trap in short (3‐ to 20‐base) single‐ and double‐stranded DNA oligomers is reviewed. Variation of 2AP’s neighboring sequence shows (1) relatively efficient transfer from adenine compared to that from cytosine and thymine, (2) efficient transfer from guanine, but only when 2AP is at the 3′ end, (3) approximate equality of efficiencies for 3′ to 5′ and 5′ to 3′ directional transfer in adenine tracks. The overall, average transfer distance at room temperature is about four adenine bases or less before de‐excitation. The transfer fluorescence excitation spectral shape is similar to that of the absorption spectrum of the neighboring normal bases, confirming that initial excitation of the normal bases, followed by emission from 2AP (i.e. energy transfer), is occurring. Transfer apparently may take place both along one strand and cross‐strand, depending on the oligomer sequence. Efficiency increases when the temperature is decreased, rising above 50% (overall efficiency) in decamers of adenine below ?60°C (frozen media). Modeling of the efficiencies of transfer from the nearest several adenine neighbors of 2AP in these oligomers suggests that the nearest two neighbors transfer with near 100% efficiency. As bases in B DNA, as well as in single‐stranded DNA, are separated by less than 5 Å (less than the size of a base), standard Förster transfer theory should not apply. Indeed, while both theory and experiment show efficiency decreasing with donor–acceptor distance, the experimental dependence clearly disagrees with Förster 1/r⁶ dependence. It is not yet clear what the best theoretical approach is, but any calculation must deal accurately with the excited states of bases, including strong base–base interactions and structural fluctuations, and should reflect the increase of efficiency with temperature decrease and the relative insensitivity to strandedness (single, double). Attempts to use DNA as a molecular “fiber optic” face three primary challenges. First, reasonable efficiency over more than a base or two occurs only in adenine stretches at temperatures well below freezing. Second, transfer in these adenine tracks is efficient in both directions. Third, absorption of UV light occurs randomly, making excitation at a specific site on this “fiber optic” a challenge.     

Is FapyG Mutagenic?: Evidence from the DFT Study

2,6‐diamino‐4‐oxo‐5‐formamidopyrimidine (FapyG) is an oxidatively damaged product of guanine (G), which is mainly formed through metabolic processes that produce OH radicals. It has been proposed that in bacterial cells, FapyG retains the coding properties of G, and is, therefore, not mutagenic. However, in mammalian cells, FapyG induces G to thymine (T) mutation more dominantly than another ubiquitous oxidative lesion, that is, 8‐oxoguanine (8‐oxoG). The exact reasons for these coding properties of FapyG are not properly understood. In order to rationalize the cause of FapyG‐mediated mutagenesis, all of the possible base‐pair interactions of FapyG with cytosine (C), adenine (A), and T, in both anti‐ and syn‐ conformations, are studied in detail by using density functional theory (DFT). The effects of solvation on the coding properties of FapyG are also evaluated. We demonstrate that the anti‐FapyG:C base pair has the highest binding energy, and that the base‐pair alignment is similar to that of the normal G:C base pair. Therefore, insertion of C opposite anti‐FapyG is preferred over the other DNA bases. This could be the reason for the non‐mutagenic behavior of FapyG in bacterial cells. However, as the binding patterns and energies of anti‐FpyG:A and syn‐FapyG:A base pairs are similar, and these are also similar to those of the T:A base pair, mammalian polymerases may not distinguish between FapyG and T. As a result, A would be mistakenly inserted opposite either anti‐FapyG or syn‐FapyG, resulting in G to T transverse mutation.