Aromaticity of H-bonded and metal complexes of guanine tautomers
- First Online:
- 1k Downloads
The effect of H-bonding and metal complexation (probed by HF, F−, Li+, Na+, and K+) on structural and π-electron delocalization changes in four most stable guanine tautomers and their structural subunits has been studied in the gas phase using the B3LYP/6−311++G(2d,2p) computational level. In both cases, i.e., H-bonding and metal complexation, the strongest interactions are found in bifurcated complexes of the keto guanine tautomers. Interactions in which the functional groups participate (NH2 or C=O) regularly lead to the greatest geometric and aromaticity changes. As a consequence, aromaticity of substituted six-membered rings is decisive for aromaticity of whole ring system in guanine tautomers. Aromaticity of guanine tautomers and their structural subunits changes in the same way (increase or decrease) depending on particular type of interactions.
KeywordsGuanine Aromaticity HOMA index Hydrogen bonding Metal cation
Guanine is one of the two purine nucleobases consisting of fused imidazole and pyrimidine (with two functional groups: oxo/hydroxo and amino/imino) rings. Among all nucleic acid bases, guanine has the largest number of tautomers—36, including rotamers [1, 2]. According to theoretical and experimental results, two keto-amino forms (7H and 9H) predominate in the gas phase [3, 4, 5, 6]. In polar solvent and for hydrated polycrystalline guanine, the 9H keto-amino tautomer is the most favored species [7, 8]. However, two enol forms of 9H guanine with cis and trans orientation of OH group are very close energetically to the 9H keto one, and all four tautomers were detected experimentally [5, 9].
In Watson–Crick pair guanine interacts with cytosine via three H-bonds  that results in proper double-stranded structure of DNA. However, quite often in RNA guanine can form pair with uracil (wobble base pair ), which has comparable thermodynamic stability to Watson–Crick base pairs . Distortion of a proper DNA structure is also induced by stabilization of rare guanine tautomers caused by metal cations [13, 14] and formation of non-Watson–Crick base pairs [15, 16]. Metal ions can also weaken [17, 18], and in some cases even disrupt , one or more hydrogen bonds in the base pairs and stabilize non-canonical structures of nucleic acids . Such interactions between metal cations and nucleobases can be direct or solvent-mediated . However, in the case of alkali metals, the X-ray investigations [22, 23] and MD simulations  support mostly direct interactions between nucleobases and partially dehydrated metal ions . Interactions with active centers of guanine located in major groove of DNA (N7 and O at C6 atom) have been discussed for years [26, 27, 28, 29, 30, 31]. More specific interactions with other centers of guanine were also described [32, 33, 34]. However, despite the extensive literature on this topic, insufficient attention to effects of intermolecular interactions with different active centers of guanine tautomers on their electronic structure has been paid.
The aim of the present work is to investigate π-electron delocalization of the most stable guanine tautomers and their complexation via H-bonding (with F−/HF) and with alkali metal cations (Li+, Na+, K+), as well as to analyze consequences of the intermolecular interactions on geometry and aromaticity of the studied systems. In this work, seven or nine active sites for the H-bonding and two or three possible sites for the metal binding were taken into account, depending on the tautomer under consideration. The sodium and potassium cations are the common ions in biological systems. A choice of the lithium cation is motivated by an opportunity to show the greatest possible changes in the electronic structure due to the strongest intermolecular interactions. To study the effect of fusion of two aromatic rings into one guanine molecule, we also performed a comparative analysis of guanine tautomers and subunits of which they are composed, in particular imidazole and substituted pyrimidine rings.
Calculations were carried out at B3LYP/6−311++G(2d,2p) level using the Gaussian 09 program . Justification of the theoretical method choice, which remains unchanged throughout our research on the effects of H-bonding and complexation with metal ions on structural and electronic properties of the nucleobases [36, 37, 38, 39], is given in our previous work .
For studied systems, optimization without any symmetry constraints was performed. Based on harmonic frequency analysis, we confirmed that all equilibrium structures correspond to true ground-state stationary points.
The second index is NICS, which was calculated: (1) in the center of the ring , NICS(0), (2) 1 Å above the center , NICS(1), and (3) the component of the tensor perpendicular to the molecular plane [46, 47], NICS(1)zz.
To gain insight into changes in electron density distribution induced by fusion of two subunits into guanine tautomers, the atomic charges were analyzed using NBO method by NBO 5.G program .
To elucidate the modification of the π-electron delocalization in studied systems, we approached different types of partners to obtain three types of complexes: (1) neutral (with HF), (2) anionic (with F−), and (3) cationic (with M+, M = Li, Na, K). The same procedure was applied to guanine tautomers and their subunits.
Results and discussion
Discussion of the results will be presented in three subsections dealing with: (1) non-interacting (free) guanine tautomers and their structural subunits (substituted pyrimidine and unsubstituted imidazole rings), (2) H-bonded complexes, and (3) complexes with alkali metal cations of the studied tautomers.
Electronic structure of free guanine tautomers
Aromaticity changes due to the fusion of subunits into guanine tautomers
In order to analyze the effect of fusion of two aromatic subunits into guanine tautomers on their electronic structure in detail, the distribution of NBO atomic charges was also studied. Even a cursory look at the atomic charges in guanine tautomers and their individual components allows us to conclude that the greatest changes occur only at the atoms of C4C5 bond shared between two fused rings, see Figs. 2S and 3S. In all tautomers, the NBO charge at C4 is always strongly positive (from 0.353 to 0.391 a.u.), whereas the charge at C5 is weakly negative (from −0.035 to −0.054 a.u.), compensating charges at neighboring atoms. For the non-fused pyrimidine rings different from the above charge distribution was found, the C4 charge is positive (from 0.091 to 0.116), and the C5 charge is strongly negative (from −0.366 to −0.403 a.u.). Moreover, if we look at the same atoms in imidazole unit, we find that both atoms, C4 and C5, are weakly negative (−0.068 and −0.088) and fusion with six-membered ring leads to their significant changes: The C4 atomic charge increases up to 0.391 a.u., and the C5 one slightly goes down to −0.035 a.u. All differences in NBO charges at other atoms in guanine tautomers and their subunits are much smaller and usually not more than 0.02 a.u. This indicates that only atoms involved in the common C4C5 bonds are the subject of substantial perturbation due to the fusion of the rings. As a result, the shared C4C5 bonds are longer in guanine tautomers than appropriate bonds in non-fused structural subunits (red numbers in Figs. 2S and 3S). The C4C5 bond lengths in guanine tautomers are between 1.390 and 1.401 Å, whereas in pyrimidine derivatives, they are between 1.361 and 1.384 Å and amounts to 1.368 Å in imidazole.
The above-described differences of the charge distributions concern fused and individual rings of the free systems. Therefore, the question arises whether they can result in different characteristic (behavior) of guanine tautomers and their structural subunits in complexes with intermolecular interactions.
Electronic structure of guanine tautomers involved in H-bonding
H-bond energies and trends in HOMA index for guanine tautomers and their subunits; E in kcal/mol
EHB (guanine tautomers)
−11.5 ÷ −13.7
−12.0 ÷ −13.2
−11.5 ÷ −14.7
−5.6 ÷ −7.3
−5.3 ÷ −6.7
−23.0 ÷ -23.9
−27.3 ÷ −27.8
−27.8 ÷ −28.3
−49.9 ÷ −50.6
−10.0 ÷ −15.9
−5.4 ÷ −5.9
−5.6 ÷ −6.0
−21.9 ÷ −23.3
−24.5 ÷ −25.4
In the case of imidazole, two types of H-bond may be formed: neutral N···HF and charge-assisted NH···F−. However, when fluoride approaches the NH moiety, the proton transfer occurs and complex with N−···HF interaction is created. The H-bond energy in such complex is equal to −28.9 kcal/mol and may be compared to strength of similar interactions with F− observed in guanine tautomers, where −23.0 ≤ EHB ≤ −23.9 kcal/mol (details in Tables 3S and 4S). Thus, in individual imidazole, this type of H-bonding is stronger than in guanine five-membered subunits by ~5 kcal/mol. It can be rationalized by a greater negative charge at the nitrogen atom in imidazole anion than in guanine one, −0.621 and −0.598 a.u., respectively. The picture is slightly different for interactions of N···HF type, where EHB(imidazole) = −13.2 kcal/mol, whereas for subunits embedded in guanine moiety, EHB is between −11.3 and −14.7 kcal/mol. In this way, for neutral H-bonds no significant differences are observed between individual five-membered ring and fused ones.
According to expectations, energy of bifurcated H-bonds is the greatest among all studied complexes. For the remainder H-bonds realized in complexes of subunits and guanine tautomers, the sequence of their strength is as follows: N−(amino)···HF > N−(ring5)···HF > O−···HF > N(ring)···HF ≈ O(keto)···HF > N(amino)···HF > O(hydroxy)···HF. Thus, charge-assisted H-bonds are stronger than the neutral ones. In the case of similar types of intermolecular interactions with a different proton acceptor atom, e.g., N−(amino)···HF and O−···HF, H-bonds with the oxygen atom are always weaker than interactions with the nitrogen atom, in line with other studies [58, 59].
Results of general comparative analysis of H-bonds formed with guanine tautomers and their structural subunits demonstrate that effect of fusion of two aromatic rings into guanine moiety is weakly pronounced and does not change significantly the strength of the H-bonds (Table 2). Data for H-bond energies agree well with results obtained recently for cytosine tautomers .
HOMA index and its changes due to H-bonding for complexes of guanine tautomers and their structural subunits
Unit 6 for g1, g2
Unit 6 for g3
Unit 6 for g4
The data for five-membered rings in guanine tautomers indicate that their aromaticity is rather insensitive to H-bonding. The differences of HOMA index between H-bonded and free species, Δ(5), are very small, unlike imidazole itself where aromaticity of the ring slightly arises due to H-bonding. The same observation has been found for six-membered rings of the most stable tautomers—g1 and g2. In the six-membered subunit alone, aromaticity increases greater than in the rings embedded in guanine moiety. In turn, for two less stable tautomers, g3 and g4, H-bonding promotes a similar decrease in aromaticity (by ~0.05 HOMA unit) for both six-membered rings (free and fused with imidazole ring). When we compare a variation of HOMA values due to the H-bond formation in guanine tautomers, we find that it is almost two times greater for six-membered rings (0.114–0.160) than for five-membered ones (0.069–0.090). This fact indicates a greater sensitivity of six-membered rings to perturbation of π-electron structure caused by H-bonding.
Furthermore, in most cases, trends in aromaticity changes found for pyrimidine part of complexes define the aromaticity changes observed in total systems. For this reason, in detailed analysis of the effect caused by different types of H-bond, we use only HOMA6 data, except the interactions, which occur only in five-membered ring, i.e., N−(ring)···HF. In all cases, trends in HOMA index for particular types of H-bond are the same for guanine tautomers and their subunits (Table 2). The weakest interactions, O(hydroxy)···HF, in g3 and g4 tautomers as well as pyrimidine subunits almost do not influence the aromaticity of complexes. However, similar interactions with the oxygen atom of the keto form in g1 and g2 tautomers have quite pronounced effect, increasing aromaticity of six-membered ring and total system due to elongation of CO bond length and disturbance of partly quinoid structure. Completely opposite effect was found for O−···HF interactions. Moreover, it has been established that greater changes in aromaticity are induced by such H-bond interactions in which functional groups such as NH2 or C=O participate. The same trend was found in H-bonded complexes of thymine and cytosine tautomers [37, 38].
Electronic structure of guanine tautomers involved in complex with metal cation
Energetic characteristics for complexes of guanine tautomers and their subunits with Na+ and trends in HOMA index; E in kcal/mol
Etot (guanine tautomers)
−44.3 ÷ −44.7
−23.1 ÷ −32.5
−30.2 ÷ −36.3
−26.7 ÷ −32.7
The greatest effect of the complexation with metal cations on aromaticity of the ring takes place for the strongest and weakest interactions. In the former case corresponding to N7,O···M+ complexes of g1, an increase in the six-membered ring aromaticity in comparison with non-interacting tautomer by 0.18, 0.16, and 0.15 HOMA unit is observed for interactions with Li+, Na+, and K+, respectively (Table 8S). This fact can be ascribed to the prevalence of the resonance structure with separated charges (Fig. 5S) which contributes to more aromatic character of the six-membered rings . On the other hand, for the g1 and g2 complexes with the weakest interactions (N3,N10···M+), the opposite changes, i.e., a decrease aromaticity of the six-membered ring by more than 0.09 HOMA unit, are found. This type of interactions also decrease the π-electron delocalization of the g1, g2 subunit ring by 0.20, 0.15, and 0.12 HOMA unit in complexes with Li+, Na+, and K+, respectively (Table 9S). Monotonic changes in aromaticity in line with the increase in metal ionic radii can be also observed.
Considering aromaticity changes caused by the formation of complexes with metal cations, it has been found that for less aromatic tautomers, g1 and g2, the greatest changes (in both directions: increase and decrease) are observed in six-membered rings, and they are responsible for total changes in aromatic character of tautomers (Table 8S). In turn, for more aromatic tautomers, g3 and g4, the complexation does not cause significant changes in aromaticity with maximum values ΔHOMA6 = 0.035 and ΔHOMA5 = 0.029. The interactions with oxygen atom of the keto tautomers (g1 and g2) lead to increase in aromaticity of the six-membered ring and the total ring system. The opposite happens in the case of interactions with O atom of the enol tautomers.
Effect of fusion of two heterocyclic structural subunits into guanine moiety on aromaticity of six- and five-membered rings is less pronounced than in the case of fusion of two rings into purine and naphthalene. However, similarly as in the case of benzene/naphthalene pair, the fusion of imidazole and pyrimidine rings with two functional groups (amino and oxo/hydroxo) into guanine leads to the elongation of the common C4C5 bond by 0.01–0.03 Å in all studied tautomers.
Aromaticity of six-membered rings and, as a consequence, aromaticity of whole guanine tautomers strongly depend on the presence of the C=O group. Tautomers with hydroxyl group (g3 and g4) are significantly more aromatic than their keto analogs (g1 and g2).
The strongest intermolecular interactions have been found in complexes of keto tautomers. In both cases, i.e., H-bonding and metal complexation, these interactions are bifurcated.
Larger changes of π-electron delocalization caused by intermolecular interactions are observed in the six-membered rings, which are also responsible for total aromaticity changes in tautomers. In all cases, trends in aromaticity changes caused by particular type of interactions are the same for guanine tautomers and their subunits.
The greatest aromaticity changes are always caused by interactions in which functional groups NH2 or C=O participate. These changes are realized in both directions—an increase and a decrease in the π-electron delocalization, expressed by HOMA index.
We thank the Foundation for Polish Science for supporting this work under MPD/2010/4 project “Towards Advanced Functional Materials and Novel Devices—Joint UW and WUT International PhD Programme” and the Interdisciplinary Center for Mathematical and Computational Modeling (Warsaw, Poland) for providing computer time and facilities.
- 14.Lippert B, Gupta D (2009) Dalton Trans 4619–4634Google Scholar
- 35.Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam MJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) GAUSSIAN 09 (Revision B.01) Gaussian Inc, Wallingford CTGoogle Scholar
- 48.Glendening ED, Badenhoop JK, Reed AE, Carpenter JE, Bohmann JA, Morales CM, Weinhold F (2004) NBO 5.G Theoretical Chemistry Institute, University of Wisconsin, Madison WIGoogle Scholar
- 55.Guille K, Clegg V (2006) Acta Cryst C62:o515–o517Google Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.