Adenine-uracil Base Pair Research Articles

The binding of diruthenium (II,III) and dirhodium (II,II) paddlewheel complexes at DNA/RNA nucleobases: Computational evidences of an appreciable selectivity toward the AU base pairs

Multiple medicinal strategies involve modifications of the structure of DNA or RNA, which disrupt their correct functioning. Metal complexes with medicinal effects, also known as metallodrugs, are among the agents intended specifically for the attack onto nucleosides. The diruthenium (II,III) and dirhodium (II,II) paddlewheel complexes constitute promising dual acting drugs due to their ability to release the therapeutically active bridging ligands upon their substitution by endogenous ligands. In this paper, we study the structure and the stability of the complexes formed by the diruthenium (II,III) and dirhodium (II,II) paddlewheel complexes coordinated in axial positions with the DNA/RNA nucleobases or base pairs, assuming the attainable metalation at all the accessible pyridyl nitrogens. Dirhodium complexes coordinate at the pyridyl nitrogens more strongly than the diruthenium complexes. On the other hand, we found that the diruthenium scaffold binds more selectively to nucleobase targets. Furthermore, we reveal a tighter coordination of diruthenium complex at the adenine-uracil base pair, compared to adenine-thymine, hence constituting a scarce instance of RNA-selectivity. We envision that the here reported computational outcomes may pace future experiments addressing the binding of diruthenium and dirhodium paddlewheel complexes at either single nucleobases or DNA/RNA fragments.

Intramolecular vibrational energy redistribution in nucleobases: Excitation of NH stretching vibrations in adenine-uracil + H2O.

Redistribution of vibrational energy in the adenine-uracil base pair is studied when the base pair undergoes an intermolecular interaction with an overtone-bending vibration excited H2O(2νbend) molecule. Energy transfer is calculated using the structural information obtained from density functional theory in the solution of the equations of motion. Intermolecular vibrational energy transfer (VET) from H2O(2νbend) to the uracil-NH stretching mode is efficient and rapidly followed by intramolecular vibrational energy redistribution (IVR) resulting from coupling between vibrational modes. An important pathway is IVR carrying energy to the NH-stretching mode of the adenine moiety in a subpicosecond scale, the energy build-up being sigmoidal, when H2O interacts with the uracil-NH bond. The majority of intermolecular hydrogen bonds between the base pair and H2O are weakened but unbroken during the ultrafast energy redistribution period. Lifetimes of intermolecular HB are on the order of 0.5ps. The efficiency of IVR in the base pair is due to near-resonance between coupled CC and CN vibrations. The resonance also exists between the frequencies of H2O bend and NH stretch, thus facilitating VET. When H2O interacts with the NH bond at the adenine end of the base pair, energy flow in the reverse direction to the uracil-NH stretch is negligible, the unidirectionality discussed in terms of the effects of uracil CH stretches. The energy distributed in the CH bonds is found to be significant. The IVR process is found to be nearly temperature independent between 200 and 400K.

Theoretical study of mechanisms for double proton transfer in adenine–uracil base pair via steered molecular dynamic simulations

Gibbs free energy profiles for the A–U ⇆ A*–U* tautomeric equilibrium between the canonical and non-canonical base pair in aqueous solution have been obtained by applying Steered Molecular Dynamic (SMD) technique. Concerted and stepwise mechanisms have been considered to explain the double proton transfer process. Among the different mechanisms studied, the stepwise mechanism was the fastest due to the lower energy barrier (∆G‡ = 31.72 kcal·mol−1) respect to the concerted process, both having a reaction energy about 25 kcal·mol−1. The inclusion of two water molecules to assist the transfer process slightly modified the reaction energy (∆G = 28.09 kcal·mol−1), while increasing the barrier considerably (∆G‡ = 65.76 kcal·mol−1). From the results obtained, we can say that the A–U pair of bases presents a Gibbs free energy profile similar to the A–T pair and that it could participate in a process of spontaneous genetic mutation depending on the mechanism followed. Finally, the stationary points along the energy profile for all the mechanisms were analyzed at molecular dynamics levels, finding that the transition states have geometries very similar to those of the products.

Real-space evidence of Watson-Crick and Hoogsteen adenine-uracil base pairs on Au(111).

From the interplay of high-resolution scanning tunneling microscopy imaging and density functional theory calculations, we show the real-space evidence of the formation of Watson-Crick and Hoogsteen adenine-uracil base pairs on an Au(111) surface with the employment of base derivatives, and further investigate the relative stability of the two types of adenine-uracil base pairs.

Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and Its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules.

Non-natural (synthetic) nucleobases, including 7-ethynyl- and 7-triazolyl-8-aza-7-deazaadenine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7-deaza modification of the adenine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanine when paired to cytosine. To stress further the H-bonding pairing in the modified adenine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.

Unraveling the Correlated Dynamics of the Double Hydrogen Bonds of Nucleic Acid Base Pairs in Solution

Quantum mechanics/molecular mechanics hybrid simulations (CPMD/GROMOS) of nonlinear infrared spectra are performed for a modified adenine-uracil base pair in CDCl(3) solution. Employing a mapping between hydrogen bond distances and fundamental as well as overtone transition frequencies on the basis of on-the-fly snapshot potential energy curves, energy gap correlation functions are established. These correlation functions are utilized to determine pump-probe and two-dimensional photon echo spectra. Analysis of the latter yields off-diagonal peaks signifying correlated fluctuations of the N-H···N and N-H···O hydrogen bonds.

Double proton transfer mechanism in the adenine–uracil base pair and spontaneous mutation in RNA duplex

We study the mechanism of double proton transfer (DPT) in the adenine–uracil (AU) base pair, both in gas phase and under the influence of surrounding water molecules. According to our ab initio calculations, no stable proton transfer product exists in gas phase, while in solution, the DPT process may occur only through the catalysis of water molecules. Nevertheless, a thermodynamic analysis confirms that AU does not contribute to spontaneous mutation in RNA duplex, and thus guanine–cytosine (GC) would be the only base pair contributing to spontaneous mutation.

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.

Effects of Microsolvation on the Adenine−Uracil Base Pair and Its Radical Anion: Adenine−Uracil Mono- and Dihydrates

Microhydration effects upon the adenine-uracil (AU) base pair and its radical anion have been investigated by explicitly considering various structures of their mono- and dihydrates at the B3LYP/DZP++ level of theory. For the neutral AU base pair, 5 structures were found for the monohydrate and 14 structures for the dihydrate. In the lowest-energy structures of the neutral mono- and dihydrates, one and two water molecules bind to the AU base pair through a cyclic hydrogen bond via the N(9)-H and N(3) atoms of the adenine moiety, while the lowest-lying anionic mono- and dihydrates have a water molecule which is involved in noncyclic hydrogen bonding via the O4 atom of the uracil unit. Both the vertical detachment energy (VDE) and adiabatic electron affinity (AEA) of the AU base pair are predicted to increase upon hydration. While the VDE and AEA of the unhydrated AU pair are 0.96 and 0.40 eV, respectively, the corresponding predictions for the lowest-lying anionic dihydrates are 1.36 and 0.75 eV, respectively. Because uracil has a greater electron affinity than adenine, an excess electron attached to the AU base pair occupies the pi* orbital of the uracil moiety. When the uracil moiety participates in hydrogen bonding as a hydrogen bond acceptor (e.g., the N(6)-H(6a)...O(4) hydrogen bond between the adenine and uracil bases and the O(w)-H(w)...N and O(w)-H(w)...O hydrogen bonds between the AU pair and the water molecules), the transfer of the negative charge density from the uracil moiety to either the adenine or water molecules efficiently stabilizes the system. In addition, anionic structures which have C-H...O(w) contacts are energetically more favorable than those with N-H...O(w) hydrogen bonds, because the C-H...O(w) contacts do not allow the unfavorable electron density donation from the water to the uracil moiety. This delocalization effect makes the energetic ordering for the anionic hydrates very different from that for the corresponding neutrals.

The Role of Reaction Force and Chemical Potential in Characterizing the Mechanism of Double Proton Transfer in the Adenine−Uracil Complex

A theoretical study of the intermolecular double proton transfer in the adenine-uracil base pair has been performed to model the double proton transfer in the adenine-thymine dimer. The mechanism is analyzed in terms of the reaction force profile, which indicates that the activation of the transfer occurs via structural rearrangements to bring the interacting molecules close to each other to let the donor and acceptor atoms in the right position to achieve the transfer. It is found that only when the first proton transfer is partially completed does the second proton get activated, thus illustrating the asynchronous nature of the double proton-transfer process in base pair systems.

Hydrogen-Atom Abstraction from the Adenine−Uracil Base Pair†

The hydrogen-abstracted radicals from the adenine-uracil (AU) base pair have been studied at the B3LYP/DZP++ level of theory. The A(N9)-U and A-U(N1) radicals, which correspond to hydrogen-atom abstraction at the adenine N9 and uracil N1 atoms, respectively, were predicted to be the two lowest-lying among the nine (AU-H) radicals studied in this study. The removal of the amino hydrogen of the adenine moiety that forms a hydrogen bond with the uracil O4 atom in the AU pair resulted in radical A(N6a)-U, which has the smallest base-pair dissociation energy, 5.9 kcal mol(-1). This radical is more likely to dissociate into the two isolated bases than to recover the hydrogen bond with the O4 atom through N6-H bond rotation along the C6-N6 bond. In general, the radicals generated by C-H bond breaking were higher in energy than those arising from N-H bond cleavage, because the unpaired electrons in the carbon-centered radicals were mainly localized on the carbon atom from which the hydrogen atom was removed. However, the highest-lying radical was found to arise from removal of the N3 hydrogen of uracil. The most remarkable structural feature of this radical is a very short C-H...O distance of 2.094 A, consistent with a substantial hydrogen bond. Although this radical lost the N1...H-N3 hydrogen bond between the two bases, its dissociation energy was predicted to be 12.9 kcal mol(-1), similar to that of the intact AU base pair. This is due to the transfer of electron density from the adenine N1 atom to the uracil N3 atom.

Energetics of the Radical Ions of the AT and AU Base Pairs: A Density Functional Theory (DFT) Study

In this work, we present DFT calculations of the energetics of the base-pair anion and cation radicals of adenine−thymine (AT) and adenine−uracil (AU). At the B3LYP/6-31+G(d) level, we find that the adiabatic electron affinities (AEAs) are 0.30 eV for AT and 0.32 eV for AU. These values are both positive but slightly smaller than previously reported values for the AEA of guanine−cytosine (GC) and the hypoxanthine−cytosine base pair (IC). Furthermore, the AT and AU anion radical vertical electron detachment energies are also smaller than those of GC and IC, with that of AT only about half of GC's. For electron transfer between two identical isolated base pairs, the reorganization energies, λ, are calculated to be AT(0.76), AU(1.06), IC(1.25), and GC(1.31 eV). These results indicate that the AT base pair has a shallow trap depth and provides a favorable route for electron transfer, which explains previous experimental results that electron-transfer rates were higher in polydAdT than in polydGdC. Values of t...

A Theoretical Investigation of Excited-State Properties of the Adenine−Uracil Base Pair

Molecular geometries of adenine−uracil (AU) base pair were optimized in the ground and selected low-lying singlet ππ* and nπ* excited states. The ground-state geometry optimized at the Hartree−Fock level of theory without symmetry restrictions was found to be planar; the predicted planarity was validated by harmonic vibrational frequency calculations. Excited states were generated employing the configuration interaction technique involving singly excited configurations (CIS method) using a ground-state-optimized geometry, and this was followed by excited-state geometry optimizations under planar symmetry. The 6-31++G(d,p) basis set was used in all calculations. The computed electronic transitions of adenine and uracil after linear scaling were found to be in good agreement with the corresponding experimental data. Electronic excitations were found to be localized at either of the monomeric units. It is predicted that among the states studied here the AU base pair has one charge transfer type singlet excit...

The Specific Solvation Effects on the Structures and Properties of Adenine−Uracil Complexes: A Theoretical ab Initio Study

Ab initio quantum chemical studies at the HF level with the 6-31G* basis set were performed for three different Watson−Crick hydrogen bonded adenine−uracil complexes in the gas phase and in a water solution approximated by the first solvation shell. Full geometry optimizations without any constraints on the planarity of these complexes were carried out. The solvent effect was modeled by explicit inclusion of seven water molecules which creates the first coordination sphere around the adenine-uracil base pair. Single point calculations were also performed at the correlated MP2/6−31*//HF/6-31G* level. The interaction and solvation energies were corrected for the basis set superposition error. It was shown that base pair corresponding to the standard Watson−Crick pair (denoted as AU1) is the lowest energy structure on the potential energy surface both in the gas phase and in a water solution. Only a slight deviation from planarity is observed for these complexes in both phases. Furthermore, the relative stab...

Monte Carlo simulations yield absolute free energies of binding for guanine—cytosine and adenine—uracil base pairs in chloroform

Monte Carlo simulations with statistical perturbation theory and the OPLS potential functions were employed to calculate the absolute free energies of binding between 9-methyladenine (A) and 1-methyluracil (U) and between 9-methylguanine (G) and 1-methylcytosine (C). The results for both AU (ca. −3.6 kcal/mol) and GC (ca. −7.9 kcal/mol) compare well with the values from experimentally determined association constants for these systems. Several thermodynamic cycles were also considered that demonstrated the high precision of the methodology.Monte Carlo simulations with statistical perturbation theory and the OPLS potential functions were employed to calculate the absolute free energies of binding between 9-methyladenine (A) and 1-methyluracil (U) and between 9-methylguanine (G) and 1-methylcytosine (C) in chloroform at 25 °C. A + U → A−U ΔG= −3.6 kcal/mol G + C → G−C ΔG= −7.9 kcal/mol

Effect of protein side chain amide group on the hydrogen-bond equilibrium in nucleobases studied by infrared and 13C-NMR spectroscopy.

Infrared spectra of 1:1 hydrogen-bonded complexes formed by derivatives of adenine and model molecules bearing the protein side chain amide group have been measured in chloroform solution. From the temperature dependence of hydrogen-bond formation, thermodynamic data on these complexes are determined. On the basis of these data, it is shown that the complexes consist of cyclic heterodimers, those that use the adenine N(1)H bond being favoured. Similarly infrared and 13C-NMR spectroscopy reveals that uracil-amide cyclic heterodimers formed through the uracil 4-carbonyl group are predominant. All of these results predict that Watson-Crick hydrogen bonds in adenine-uracil base-pairs may be opened to some extent, as proved in this work. The possible biological importance of these observations is also discussed.

Complex formation of adenine-uracil base pair with some transition metal ions

Mixed complexes of Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) ions with 6-aminopurine (adenine, ADN) and uracil (URL) were prepared from aqueous ethanol solution at pH about 7. The new complexes have the formulae M 2(ADNURL)(OH) 2·H 2O for M = Mn(II), Zn(II), Cd(II) and M 2(ADNURL)(OH) 4·3H 2O for M = Co(II), Ni(II), Cu(II). The mixed complexes were characterized by elemental, infrared, electronic, ESR spectral and magnetic measurements. ADN behaves as a bidentate ligand. The probable binding sites of ADN are N 3 and N 7 nitrogens and of URL is C 2O. Polymeric structures have been suggested with ADN and OH as the bridging ligands.

Theoretical studies on the interaction of proteins with base pairs. I. Ab initio calculation for the effect of H‐bonding interaction of proteins on the stability of adenine–uracil pair

AbstractThe hydrogen‐bonding interaction of protein with the adenine–uracil base pair was investigated by the ab initio MO method (STO‐3G level). We found that the stability of the base pair was greatly affected by the hydrogen‐bonding interaction of several residues of protein in different ways, depending on whether the interacting species is charged or neutral, whether the interaction is made from the major groove or minor groove side, and which of the two, adenine or uracil, is hydrogen bonded. These results were interpreted as the cooperative interaction between the base pair hydrogen bonds and external ones. The implications of the present results to biological functions were also discussed.

All-valence-electrons bond index en the h bond of watson-crick pairs

The normal Watson-Crick base pairs are treated as supermolecules. The properties of the electron distribution along the N-H⋯Y bonds are studied in an all-valence-electrons calculation, through a bond index formula devised for a nonorthogonal basis. Electronic density diagrams of the adenine-uracil base pair are analysed.

RNA double-helical fragments at atomic resolution: I. The crystal and molecular structure of sodium adenylyl-3′,5′-uridine hexahydrate

The crystal structure of sodium adenylyl-3′,5′-uridine (ApU) hexahydrate has been determined by X-ray diffraction procedures and refined to an R factor of 0.057. ApU crystallizes with two molecules per asymmetric unit in a monoclinic unit cell, space group P2 1, with cell dimensions: a = 18.025, b = 17.501, c = 9.677 A ̊ and β = 99.45 ° . The two independent molecules of ApU form a small segment of right-handed antiparallel double-helical RNA in the crystal, with Watson-Crick base-pairing between adenine and uracil. This is the first time that this Watson-Crick base-pair has been seen unambiguously at atomic resolution and it is also the first time that a nucleic acid fragment with double-helical symmetry has been seen at atomic resolution. The distance between the C1′ atoma of the adenine-uracil base-pair is slightly shorter than the analogous distance seen in guanine-cytosine base-pairs. The bases in each strand are heavily stacked. One sodium cation binds to the phosphates, as expected; however, the other sodium cation binds on the dyad axis in the minor groove of the double helix. It is co-ordinated directly to the two uracil carbonyl groups which protrude into the minor groove and is shielded from the nearest phosphates by a shell of water. This binding appears to be sequence-specific for ApU. One of the adenines also forms a pair of hydrogen bonds to a nearby ribose, utilizing N6 and N7. The 12 water molecules per double-helical fragment are all part of the first co-ordination shell. The ions and the symmetry of the double-helical fragment are the major organizing elements of the solvent region.