Low‐Energy‐Barrier Proton Transfer Induced by Electron Attachment to the Guanine⋅⋅⋅Cytosine Base Pair

The photoelectron spectrum of the anion of the guanine ??? cytosine base apair (GC)^.? is recorded for the first time. The observed variation in the spectral peak‐height ratios with the source conditions suggests the presence of two or more anionic isomers. Two maxima of the broad bands in the photoelectron spectrum were measured at about 1.9 and about 2.6 eV. These values are very well reproduced by the vertical detachment energies of the B3LYP/6‐31++G(d,p) calculated low‐energy anionic structures, which are 1) the Watson–Crick base‐pair anion with proton transferred from N1 of guanine to N3 of cytosine, 2) its analogue in which the proton is transferred from N9 of guanine to N7 of guanine, and 3) the global minimum geometry, which is formed from the latter anion by rotation of guanine about the axis approximately defined by C2 of guanine and C4 of cytosine. Furthermore, a minor difference in the stabilities of the two lowest energy anions explains the experimentally observed source (temperature) dependence of the PES spectrum. A rational procedure, based on the chemistry involved in the formation of anionic dimers, which enables the low‐energy anions populated in the photoelectron spectrum to be identified is proposed. In contrast to the alternative combinatorial approach, which in the studied case would lead to carrying out quantum chemical calculations for 2000–2500 structures, the procedure described here reduces the computational problem to only 15 geometries.     

Effects of OH radical addition on proton transfer in the guanine-cytosine base pair

Double proton transfer (PT) reactions in guanine-cytosine OH radical adducts are studied by the hybrid density functional B3LYP approach. Concerted and stepwise proton-transfer processes are explored between N1(H) on guanine (G) and N3 on cytosine (C), and between N4(H) on C and O6 on G. All systems except GC6OH display a concerted mechanism. 8OHGC has the highest dissociation energy and is 1.2 kcal/mol more stable than the nonradical GC base pair. The origin of the interactions are investigated through the estimation of intrinsic acid-basic properties of the *OH-X monomer (X = G or C). Solvent effects play a significant role in reducing the dissociation energy. The reactions including *OH-C adducts have significantly lower PT barriers than both the nonradical GC pair and the *OH-G adducts. All reactions are endothermic, with the GC6OH --> GC6OHPT reaction has the lowest reaction energy (4.6 kcal/mol). In accordance with earlier results, the estimated NBO charges show that the G moiety carries a slight negative charge (and C a corresponding positive one) in each adduct. The formation of a partial ion pair may be a potential factor leading to the PT reactions being thermodynamically unfavored.     

Base-pair interactions in the gas-phase proton-bonded complexes of C+G and C+GC

Interactions involved in the formation of gas-phase proton-bonded molecular complexes of cytosine (C) and guanine (G) were theoretically investigated for the case of C(+)G and C(+)GC using B3LYP density functional theory. In this study, particular focus was on the dimeric interaction of proton-bonded C(+)G, where a proton bond and a hydrogen bond are cooperatively involved. The dimer interaction energy in terms of dissociation energy (D(e)) was predicted to be 41.8 kcal/mol. The lowest (frozen) energy structure for the C(+)G dimeric complex was found to be CH(+)...G rather than C...H(+)G in spite of the lower proton affinity of the cytosine moiety, which was more stable by 3.3 kcal/mol. The predicted harmonic vibrational frequencies and bond lengths suggest that the combined contributions of proton and hydrogen bonding may determine the resultant stability of each complex structure. In contrast to the dimer case, in the case of the isolated C(+)GC triplet, the two minimum energy structures of CH(+)...GC and C...H(+)GC were predicted to be almost equivalent in total energy. The dissociation energy (D(e)) for the C(+)G pairing in the C(+)GC triplet was 43.7 kcal/mol. Other energetics are also reported. As for the proton-transfer reaction in the proton-bond axis, the forward proton-transfer barriers for the dimer and trimer complexes were also predicted to be very low, 3.6 and 1.5 kcal/mol (DeltaE(e)(PT)), respectively.     

Marked variations of dissociation energy and H-bond character of the guanine-cytosine base pair induced by one-electron oxidation and Li+ cation coupling

The variation of dissociation energy and H-bond character of the G-C cation and the Li-GC cation have been investigated by employing density functional theory (B3LYP) with the 6-31+G* basis set. The one-electron oxidation and the coupling of Li(+) to the guanine-cytosine base pair can strengthen the interaction between guanine and cytosine. The interaction of the cation Li(+) with guanine is attractive and is attributed to the polarization of the H-bonds between G-C that enhances G-C interaction. The cooperativity of the three H-bonds in the GC and Li-GC cations is different from that in the neutral GC base pair. The proton-transfer process between N(1) of the guanine and N(3) of the cytosine can occur in the GC cation and the Li-GC cation. The geometries of the transition state are out of plane, especially for the transition state of the Li-GC cation. The analysis of the activation energy for the proton-transfer process shows that the GC(+) before and after proton transfer can exist simultaneously in the gas phase, but for the Li-GC(+) system, the Li-GC(+) without proton transfer is the dominating species in the gas phase.     

Microhydration of the guanine-cytosine (GC) base pair in the neutral and anionic radical states: a density functional study

A density functional study of the effects of microhydration on the guanine-cytosine (GC) base pair and its anion radical is presented. Geometries of the GC base pair in the presence of 6 and 11 water molecules were fully optimized in the neutral (GC-nH2O) and anion radical [(GC-nH2O)*-] (n = 6 and 11) states using the B3LYP method and the 6-31+G** basis set. Further, vibrational frequency analysis at the same level of theory (B3LYP/6-31+G**) was also performed to ensure the existence of local minima in these hydrated structures. It was found that water molecules surrounding the GC base pair have significant effects on the geometry of the GC base pair and promote nonplanarity in the GC base pair. The calculated structures were found to be in good agreement with those observed experimentally and obtained in molecular dynamics (MD) simulation studies. The water molecules in neutral GC-nH2O complexes lie near the ring plane of the GC base pair where they undergo hydrogen bonding with both GC and each other. However, in the GC anion radical complexes (GC-nH2O, n = 6, 11), the water molecules are displaced substantially from the GC ring plane. For GC-11H2O*-, a water molecule is hydrogen-bonded with the C6 atom of the cytosine base. We found that the hydration shell initially destabilizes the GC base pair toward electron capture as a transient anion. Energetically unstable diffuse states in the hydration shell are suggested to provide an intermediate state for the excess electron before molecular reorganization of the water molecules and the base pair results in a stable anion formation. The singly occupied molecular orbital (SOMO) in the anion radical complexes clearly shows that an excess electron localizes into a pi orbital of cytosine. The zero-point-energy (ZPE-) corrected adiabatic electron affinities (AEAs) of the GC-6H2O and GC-11H2O complexes, at the B3LYP/6-31+G** level of theory, were found to be 0.74 and 0.95 eV, respectively. However, the incorporation of bulk water as a solvent using the polarized continuum model (PCM) increases the EAs of these complexes to 1.77 eV.     

Electron affinity of the guanine-cytosine base pair and structural perturbations upon anion formation

The adiabatic electron affinity (AEA) for the Watson-Crick guanine-cytosine (GC) DNA base pair is predicted using a range of density functional methods with double- and triple-zeta plus polarization plus diffuse (DZP++ and TZ2P++) basis sets in an effort to bracket the true electron affinity. The methods used have been calibrated against a comprehensive tabulation of experimental electron affinities (Chem.Rev. 2002, 102, 231). Optimized structures for GC and the GC anion are compared to the neutral and anionic forms of the individual bases as well as Rich's 1976 X-ray structure for sodium guanylyl-3',5'-cytidine nonahydrate, GpC.9H(2)O. Structural distortions and natural population (NPA) charge distributions of the GC anion indicate that the unpaired electron is localized primarily on the cytosine moiety. Unlike treatments using second-order perturbation theory (MP2), density functional theory consistently predicts a substantial positive adiabatic electron affinity for the GC pair (e.g., TZ2P++/B3LYP: +0.48 eV). The stabilization of C(-) via three hydrogen bonds to guanine is sufficient to facilitate adiabatic binding of an electron to GC and is also consistent with the positive experimental electron affinities obtained by photoelectron spectroscopy of cytosine anions incrementally microsolvated with water molecules. The pairing (dissociation) energy for GC(-) (35.6 kcal/mol) is determined with inclusion of electron correlation and shows the anion to have greater thermodynamic stability; the pairing energy for neutral GC (TZ2P++/B3LYP 23.9 kcal/mol) compares favorably to previous MP2/6-31G (23.4 kcal/mol) results and a debated experiment (21.0 kcal/mol).     

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.     

H-bonding patterns in the platinated guanine-cytosine base pair and guanine-cytosine-guanine-cytosine base tetrad: an electron density deformation analysis and AIM study

The atoms in molecule theory (AIM) and electronic structure analysis are applied together to investigate H-bonding patterns in metalated nucleobase complexes. The influence of Pt on the intra GC base pair H-bonding has been found to reduce intra base pair H-bonding of N4(C)...O6(G) in the platinated GC pair and GCGC tetrad. The relaxation of geometry constrains in metalated nucleobases is found to be decisively important in the formation of novel molecular architectures from nucleobases and metal entities. The incorporation of the platinum in the GCGC tetrad benefits the formation of the unique CH...N (H5(C)...N1(G)) hydrogen bond pattern in the tetrad by offering improved geometric constraints rather than through changing the electronic properties around the H5(C) and N1(G) sites. Platination at the N7 of guanine reduces the deprotonation energy considerably.     

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.     

The hydrogen bonding properties of cytosine: a computational study of cytosine complexed with hydrogen fluoride, water, and ammonia

Density functional theory is used to study the hydrogen bonding pattern in cytosine, which does not contain alternating proton donor and acceptor sites and therefore is unique compared with the other pyrimidines. Complexes between various small molecules (HF, H(2)O, and NH(3)) and four main binding sites in (neutral and (N1) anionic) cytosine are considered. Two complexes (O2(N1) and N3(N4)) involve neighboring cytosine proton acceptor and donor sites, which leads to cooperative interactions and bidendate hydrogen bonds. The third (less stable) complex (N4) involves a single cytosine donor. The final (O2-N3) complex involves two cytosine proton acceptors, which leads to an anticooperative hydrogen bonding pattern for H(2)O and NH(3). On the neutral surface, the anticooperative O2-N3 complex is less stable than those involving bidentate hydrogen bonds, and the H(2)O complex cannot be characterized when diffuse functions are included in the (6-31G(d,p)) basis set. On the contrary, the anionic O2-N3 structure is the most stable complex, while the HF and H(2)O N3(N4) complexes cannot be characterized with diffuse functions. B3LYP and MP2 potential energy surface scans are used to consider the relationship between the water N3(N4) and O2-N3 complexes. These calculations reveal that diffuse functions reduce the conversion barrier between the two complexes on both the neutral and anionic surfaces, where the reduction leads to a (O2-N3) energy plateau on the neutral surface and complete (N3(N4)) complex destabilization on the anionic surface. From these complexes, the effects of hydrogen bonds on the (N1) acidity of cytosine are determined, and it is found that the trends in the effects of hydrogen bonds on the (N1) acidity are similar for all pyrimidines.     

Effect of nucleobase sequence on the proton-transfer reaction and stability of the guanine-cytosine base pair radical anion

The formation of base pair radical anions is closely related to many fascinating research fields in biology and chemistry such as radiation damage to DNA and electron transport in DNA. However, the relevant knowledge so far mainly comes from studies on isolated base pair radical anions, and their behavior in the DNA environment is less understood. In this study, we focus on how the nucleobase sequence affects the properties of the guanine-cytosine (GC) base pair radical anion. The energetic barrier and reaction energy for the proton transfer along the N(1)(G)-H···N(3)(C) hydrogen bond and the stability of GC˙(-) (i.e., electron affinity of GC) embedded in different sequences of base-pair trimer were evaluated using density functional theory. The computational results demonstrated that the presence of neighboring base pairs has an important influence on the behavior of GC˙(-) in the gas phase. The excess electron was found to be localized on the embedded GC and the charge leakage to neighboring base pairs was very minor in all of the investigated sequences. Accordingly, the sequence behavior of the proton-transfer reaction and the stability of GC˙(-) is chiefly governed by electrostatic interactions with adjacent base pairs. However, the effect of base stacking, due to its electrostatic nature, is severely screened upon hydration, and thus, the sequence dependence of the properties of GC˙(-) in aqueous environment becomes relatively weak and less than that observed in the gas phase. The effect of geometry relaxation associated with neighboring base pairs as well as the possibility of proton transfer along the N(2)(G)-H···O(2)(C) channel have also been investigated. The implications of the present findings to the electron transport and radiation damage of DNA are discussed.     

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.     

cis-Diamminodichloronickel and Its Interaction with Guanine and Guanine–Cytosine Base Pair

Comprehensive ab initio calculations are performed on cis-diamminodichloronickel (cisni) at the HF, DFT, and MP2 levels of theory. The results are compared to those obtained for cisplatin. The characteristics of the interactions of cisni with guanine (G) and guanine–cytosine (GC) base pair are also evaluated and compared to the interactions of cisplatin. Cisni causes similar geometric changes of the base as cis-platinum when complexed to guanine. The nickel, palladium and platinum complexes also show similar characteristics when complexed to GC base pair. However, this study predicts higher dissociation energy of the cisni chlorine ligands that indicate areas of differences between the title Ni and Pt and Pd complexes. Comparison of the G-cisni interaction energy to that of cisplatin and cispd indicate differences between the Ni and Pd complexes, but also reveals its closer similarities to cisplatin.     

The Topological Analysis of the ELFx Localization Function: Quantitative Prediction of Hydrogen Bonds in the Guanine–Cytosine Pair

In this contribution, we recall and test a new methodology designed to identify the favorable reaction pathway between two reactants. Applied to the formation of the DNA guanine (G) –cytosine (C) pair, we successfully predict the best orientation between the base pairs held together by hydrogen bonds and leading to the formation of the typical Watson Crick structure of the GC pair. Beyond the global minimum, some local stationary points of the targeted pair are also clearly identified.     

Combined QM(DFT)/MM molecular dynamics simulations of the deamination of cytosine by yeast cytosine deaminase (yCD)

Extensive combined quantum mechanical (B3LYP/6‐31G*) and molecular mechanical (QM/MM) molecular dynamics simulations have been performed to elucidate the hydrolytic deamination mechanism of cytosine to uracil catalyzed by the yeast cytosine deaminase (yCD). Though cytosine has no direct binding to the zinc center, it reacts with the water molecule coordinated to zinc, and the adjacent conserved Glu64 serves as a general acid/base to shuttle protons from water to cytosine. The overall reaction consists of several proton‐transfer processes and nucleophilic attacks. A tetrahedral intermediate adduct of cytosine and water binding to zinc is identified and similar to the crystal structure of yCD with the inhibitor 2‐pyrimidinone. The rate‐determining step with the barrier of 18.0 kcal/mol in the whole catalytic cycle occurs in the process of uracil departure where the proton transfer from water to Glu64 and nucleophilic attack of the resulting hydroxide anion to C2 of the uracil ring occurs synchronously. © 2016 Wiley Periodicals, Inc.     

Electron attachment to a hydrated DNA duplex: the dinucleoside phosphate deoxyguanylyl-3',5'-deoxycytidine

The minimal essential section of DNA helices, the dinucleoside phosphate deoxyguanylyl-3',5'-deoxycytidine dimer octahydrate, [dGpdC](2), has been constructed, fully optimized, and analyzed by using quantum chemical methods at the B3LYP/6-31+G(d,p) level of theory. Study of the electrons attached to [dGpdC](2) reveals that DNA double strands are capable of capturing low-energy electrons and forming electronically stable radical anions. The relatively large vertical electron affinity (VEA) predicted for [dGpdC](2) (0.38 eV) indicates that the cytosine bases are good electron captors in DNA double strands. The structure, charge distribution, and molecular orbital analysis for the fully optimized radical anion [dGpdC](2)(·-) suggest that the extra electron tends to be redistributed to one of the cytosine base moieties, in an electronically stable structure (with adiabatic electron affinity (AEA) 1.14 eV and vertical detachment energy (VDE) 2.20 eV). The structural features of the optimized radical anion [dGpdC](2)(·-) also suggest the probability of interstrand proton transfer. The interstrand proton transfer leads to a distonic radical anion [d(G-H)pdC:d(C+H)pdG](·-), which contains one deprotonated guanine anion and one protonated cytosine radical. This distonic radical anion is predicted to be more stable than [dGpdC](2)(·-). Therefore, experimental evidence for electron attachment to the DNA double helices should be related to [d(G-H)pdC:d(C+H)pdG](·-) complexes, for which the VDE might be as high as 2.7 eV (in dry conditions) to 3.3 eV (in fully hydrated conditions). Effects of the polarizable medium have been found to be important for increasing the electron capture ability of the dGpdC dimer. The ultimate AEA value for cytosine in DNA duplexes is predicted to be 2.03 eV in aqueous solution.     

B型DNA中鸟嘌呤-胞嘧啶碱基对内双质子转移反应

采用ONIOM(M06-2X/6-31G^*:PM3)方法研究了单个鸟嘌呤-胞嘧啶(GC)碱基对和含GC碱基对的四种排序的DNA三聚体(dATGCAT, dGCGCGC, dTAGCTA, dCGGCCG)的双质子转移反应. 通过分析其双质子转移方式、质子转移过程中各结构的能量和氢键变化, 总结出环境因素对GC碱基对双质子转移机理的影响. 气相中, dCGGCCG三聚体中发生分步双质子转移, 其它四种模型中均发生协同双质子转移. 分析发现质子转移方式受上下相邻碱基对的静电相互作用和质子接受位的质子亲和势影响, dATGCAT和dGCGCGC排序有助于质子H4a转移, 而dTAGCTA和dCGGCCG排序有助于质子H1转移, 胞嘧啶的N3位较高的质子亲和势有助于质子H1转移. 水溶剂中, 上下相邻碱基对的静电相互作用被减弱, 水溶剂稳定了分步转移过程中的单质子转移产物, 因此分步转移机理占据优势, 五种模型中均出现分步双质子转移, 在此过程中能量变化趋势相似. 溶剂效应有利于单质子转移, 却增加了双质子转移反应的反应能.     

Theoretical study of tautomeric and ionizing effects of guanine,cytosine, and their methyl derivatives

The study of pre-translational effects (ionization, tautomerization) and post-translational effects (methylation) of guanine and cytosine has only recently been the focus of some studies. These effects can potentially help regulate gene expression as well as potentially disrupt normal gene function. Because of this wide array of roles, greater insight into these effects in deoxyribonucleic acids (DNA) are paramount. There has been considerable research of each phenomenon (tautomerization, methylation and ionization) individually. In this work, we attempt to shed light upon the pre- and post-translational effects of guanine and cytosine by investigating the electron affinities (EAs) and ionization potentials (IPs) of the major and minor tautomers and their methyl derivatives. We performed all calculations using the density functional theory B3LYP functional accompanied with 6-311G (d,p), 6-311+G (d,p), and 6-311++G (df,pd) basis sets. Our results reveal that the cytosine tautomer has a higher EA and IP than the guanine tautomers. The higher EA suggest that an electron that attaches to the GC base pair would predominately attach to the cytosine instead of guanine. The higher IP would suggest that an electron that is removed from the GC base pair would be predominately removed from the guanine within the base pair. Understanding how tautomerization, ionization, and methylation differences change effects, discourages, or promotes one another is lacking. In this work, we begin the steps of integrating these effects with one another, to gain a greater understanding of molecular changes in DNA bases.     

On the evolution of one-electron-oxidized deoxyguanosine in damaged DNA under physiological conditions: a DFT and ONIOM study on proton transfer and equilibrium

Different deprotonation paths of the radical cation formed by one-electron oxidation of 2'-deoxyguanosine (2dG) sites in DNA have been studied using Density Functional Theory (M05-2X/6-31+G(d,p)) and ONIOM methodology (M05-2X/6-31+G(d,p):PM6) in conjunction with the SMD model to include the solvent effects. Models of increased complexity have been used ranging from the isolated nucleoside to a three unit double-stranded oligomer including the sugar units, the base pairing with cytidine, and the phosphate linkage. The reported results correspond to aqueous solution, at room temperature, and pH = 7.4. Under such conditions it was found that the proton transfer (PT) within the base pair is a minor path compared to the PT between the base pair and the surrounding water. It was also found that the deprotonation of ground-state 2dG˙(+) sites mainly yields C centered radicals in the sugar unit, with the largest populations corresponding to C4'˙ and C5'˙, followed by C3'˙. The different aspects of the presented theoretical study have been validated with experimental results.     

Successive attachment of electrons to protonated Guanine: (G+H)* radicals and (G+H)- anions

The structures, energetics, and vibrational frequencies of nine hydrogenated 9H-keto-guanine radicals (G+H)(*) and closed-shell anions (G+H)(-) are predicted using the carefully calibrated (Chem. Rev. 2002, 102, 231) B3LYP density functional method in conjunction with a DZP++ basis set. These radical and anionic species come from consecutive electron attachment to the corresponding protonated (G+H)(+) cations in low pH environments. The (G+H)(+) cations are studied using the same level of theory. The proton affinity (PA) of guanine computed in this research (228.1 kcal/mol) is within 0.7 kcal/mol of the latest experiment value. The radicals range over 41 kcal/mol in relative energy, with radical r1, in which H is attached at the C8 site of guanine, having the lowest energy. The lowest energy anion is a2, derived by hydride ion attachment at the C2 site of guanine. No stable N2-site hydride should exist in the gas phase. Structure a9 was predicted to be dissociative in this research. The theoretical adiabatic electron affinities (AEA), vertical electron affinities, and vertical detachment energies were computed, with AEAs ranging from 0.07 to 3.12 eV for the nine radicals.