An ab initio molecular orbital study on the stacking interaction between nucleic acid bases: Dependence on the sequence and relation to the conformation

The stacking interaction energies between nucleic acid bases in A DNA and B DNA are calculated by means of the ab initio molecular orbital method. The calculated values agree well with the experimental values of stacking enthalpy changes. The stacking interaction energy is shown to be highly sequence dependent, particularly when the sequence includes guanine or cytosine. The possibility is shown that the conformation of a DNA double helix fragment is determined by the constituent stacking interaction. Electrostatic energy is the cause of the sequence dependency of the stacking energy, while charge transfer and dispersion energies contribute to the overall stability.     

Characterization of nucleobase-amino acid stacking interactions utilized by a DNA repair enzyme

The present work characterizes the gas-phase stacking interactions between four aromatic amino acid residues (histidine, phenylalanine, tyrosine, and tryptophan) and adenine or 3-methyladenine due to the proposed utilization of these interactions by enzymes that repair DNA alkylation damage. The MP2 potential energy surfaces of the stacked dimers are considered as a function of four variables (vertical displacement, angle of rotation, horizontal displacement, and tilt angle) using a variety of basis sets. It is found that the maximum stacking interaction energy decreases with the amino acid according to TRP > TYR approximately HIS > PHE for both nucleobases. However, the magnitude of the stacking interaction significantly increases upon alkylation (by 50-115%). Comparison of the stacking energies calculated using our surface scans to those estimated from experimental crystal structures indicates that the stacking interactions within the active site of 3-methyladenine DNA glycosylase can account for 65-75% of the maximum possible stacking interaction between the relevant molecules. The decrease in stacking in the crystal structure arises due to significant differences in the relative orientations of the nucleobase and amino acid. Nevertheless, alkylation is found to significantly increase the stacking energy when the crystal structure geometries are considered. Our calculations provide computational support for suggestions that alkylation enhances the stacking interactions within the active site of DNA repair enzymes, and they give a measure of the magnitude of this enhancement. Our results suggest that alkylation likely plays a more important role in substrate identification and removal than the nature of the aromatic amino acid that interacts with the substrate via stacking interactions.     

Interaction between uracil nucleobase and phenylalanine amino acid: the role of sodium cation in stacking

The stacking interactions in the uracil:phenylalanine (U:PHE) and (U:PHE)···Na⁺ complexes have been studied at different levels of theory, in which the structures were optimized by both standard and gradient counterpoise corrected methods. The Na⁺ cation can interact with different sites of stacked U:PHE unit. The geometrical parameters of the optimized structures and the calculated binding energies reveal the influence of cation interaction on π–π stacking and vice versa. The interplay between π–π stacking and cation interaction has also been investigated by topological analysis of electron charge density using atoms in molecules (AIM) method. A good agreement between the results of AIM analysis and calculated binding energies has been observed in dimer and complexes.     

A computational characterization of the hydrogen-bonding and stacking interactions of hypoxanthine

The hydrogen-bonding and stacking interactions of hypoxanthine, a potential universal nucleobase, were calculated using a variety of methodologies (CCSD(T), MP2, B3LYP, PWB6K, AMBER). All methods predict that the hydrogen-bonding interaction in the hypoxanthine-cytosine pair is approximately 25 kJ mol(-1) stronger than that in the other dimers. Although the calculations support suggestions from experiments that hypoxanthine preferentially binds with cytosine, the trend in the calculated hydrogen-bond strengths for the remaining natural nucleobases do not show a strong correlation with the experimentally predicted binding preferences. However, our calculations suggest that the stacking interactions of hypoxanthine are similar in magnitude to the hydrogen-bonding interactions at all levels of theory (with the exception of B3LYP, which incorrectly predicts stacked dimers to be unstable). Therefore, stacking interactions should also be considered when analyzing the stability of DNA helices containing hypoxanthine and the use of larger models that account for both hydrogen-bonding and stacking within DNA duplexes will likely result in better agreement with experimental observations. For the majority of the dimers, PWB6K and AMBER provide reasonable binding strengths at reduced computational costs, and therefore will be useful techniques for considering larger models.     

Twist‐dependent stacking energy of base‐pair steps in B‐DNA geometry: A density functional theory approach

Stacking energy of all the 10 unique DNA base‐pair steps (bp step) are calculated using density functional theory within the ultrasoft pseudopotential plane wave method and local density approximation for the exchange‐correlation functional. We have studied the dependence of stacking energy on twist angle, an aspect found difficult to explain using classical theory. We have found that the twist angle for different bp steps at stacking energy minimum matches extremely well with the values of average twist obtained from B‐DNA crystal structure data. This indicates that the use of a proper quantum chemical method to calculate the π‐π electronic interactions may explain stacking energy without incorporating hydrophobic interaction through solvent or effect of backbone through pseudobond. From the twist angle‐dependent stacking energy profile, we have also generated the probability distributions of twist for all the bp steps and calculated the variance of the distribution. Our calculated variances show similar trend to that of the experimental data for which sufficient numbers of data are available. The TA, AT, and CG doublets show large variances among the 10 possible bp steps, indicating their maximum flexibility. This might be the case of unusual deformation observed at the TATA‐box while binding to TBP protein. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

X-ray diffraction from faulted cellulose I constructed with mixed Iα–Iβ stacking

Cellulose from higher plants is usually thought to be a composite of the Iα and Iβ allomorphs, with predominance of the latter. Instead of the pure allomorphs, this article proposes that Iα and Iβ stacking patterns coexist within each crystallite, forming a type of crystallographic defect known as stacking fault. Models of faulted crystallites are constructed with mixed Iα–Iβ stacking and their X-ray diffraction intensities are calculated using the Diffracted Intensities From Faulted Xtals (DIFFaX) computer program. Simulated powder diffractograms from faulted crystallites compare favorably with experimental data, modifying diffractogram regions that have been misfit by models based on the Iβ crystal structure. Calculations also reveal that stacking faults generate a signature in the (hkl) dependence of diffraction line broadening, guiding further experimental verification and eventual quantification of stacking faults. Our findings bring an alternative view of native cellulose polymorphism and suggest that the proposed stacking faults are ubiquitous crystallographic defects in cellulose from higher plants.     

Understanding the role of base stacking in nucleic acids. MD and QM analysis of tandem GA base pairs in RNA duplexes

Preceding NMR experiments show that the conformation of tandem GA base pairs, an important recurrent non-canonical building block in RNA duplexes, is context dependent. The GA base pairs adopt "sheared" N3(G)-N6(A), N2(G)-N7(A) geometry in the r(CGAG)(2) and r(iGGAiC)(2) contexts while switching to "imino" N1(G)-N1(A), O6(G)-N6(A) geometry in the r(GGAC)(2) and r(iCGAiG)(2) contexts (iC and iG stand for isocytosine and isoguanine, respectively). As base stacking is likely to be one of the key sources of the context dependence of the conformation of GA base pairs, we calculated base stacking energies in duplexes containing such base pairs, to see if this dependence can be predicted by stacking energy calculations. When investigating the context dependence of the GA geometry two different conformations of the same duplex were compared (imino vs. sheared). The geometries were generated via explicit solvent MD simulations of the respective RNA duplexes, while the subsequent QM energy calculations focused on base stacking interactions of the four internal base pairs. Geometrical relaxation of nucleobase atoms prior to the stacking energy computations has a non-negligible effect on the results. The stacking energies were derived at the DFT-D/6-311++G(3df,3pd) level. We show a rather good correspondence between the intrinsic gas-phase stacking energies and the NMR-determined GA geometries. The conformation with more favorable gas-phase stacking is in most cases the one observed in experiments. This correlation is not improved when including solvent effects via the COSMO method. On the other side, the stacking calculations do not predict the relative thermodynamic stability of duplex formation for different sequences.     

A computational proposal for the experimentally observed discriminatory behavior of hypoxanthine, a weak universal nucleobase

A computational model composed of six nucleobases was used to investigate why hypoxanthine does not yield duplexes of equal stability when paired opposite each of the natural DNA nucleobases. The magnitudes of all nearest-neighbor interactions in a DNA helix were calculated, including hydrogen-bonding, intra- and interstrand stacking interactions, as well as 1-3 intrastrand stacking interactions. Although the stacking interactions in DNA relevant arrangements are significant and account for at least one third of the total stabilization energy in our nucleobase complexes, the trends in the magnitude of the stacking interactions cannot explain the relative experimental melting temperatures previously reported in the literature. Furthermore, although the total hydrogen-bonding interactions explain why hypoxanthine preferentially pairs with cytosine, the experimental trend for the remaining nucleobases (A, T, G) is not explained. In fact, the calculated pairing preference of hypoxanthine matches that determined experimentally only when the sum of all types of nearest-neighbor interactions is considered. This finding highlights a strong correlation between the relative magnitude of the total nucleobase-nucleobase interactions and measured melting temperatures for DNA strands containing hypoxanthine despite the potential role of other factors (including hydration, temperature, sugar-phosphate backbone). By considering a large range of sequence combinations, we reveal that the binding preference of hypoxanthine is strongly dependent on the nucleobase sequence, which may explain the varied ability of hypoxanthine to universally bind to the natural bases. As a result, we propose that future work should closely examine the interplay between the dominant nucleobase-nucleobase interactions and the overall strand stability to fully understand how sequence context affects the universal binding properties of modified bases and to aid the design of new molecules with ambiguous pairing properties.     

Geometry and electronic structure of rhombohedral C60 polymer

Geometry and electronic structure of the rhombohedral C₆₀ polymer are studied by means of density-functional theory (DFT) within the local-density-approximation (LDA). It is found that stacking sequence proposed by Chen et al. is more stable than the original model by Núñez-Regueiro et al., although the energy difference between the two is very small. The material is a semiconductor with the LDA gap of 0.68 eV. Conduction bands show dependence on the way of stacking, and density of states has a sharp peak at the conduction bottom. Bond lengths are also calculated and found to be in good agreement with the results of the X-ray structure analysis.     

Efficient calculation of many stacking and pairing free energies in DNA from a few molecular dynamics simulations

Through the use of the one-step perturbation approach, 130 free energies of base stacking and 1024 free energies of base pairing in DNA have been calculated from only five simulations of a nonphysical reference state. From analysis of a diverse set of 23 natural and unnatural bases, it appears that stacking free energies and stacking conformations play an important role in pairing of DNA nucleotides. On the one hand, favourable pairing free energies were found for bases that do not have the possibility to form canonical hydrogen bonds, while on the other hand, good hydrogen-bonding possibilities do not guarantee a favourable pairing free energy if the stacking of the bases dictates an unfavourable conformation. In this application, the one-step perturbation approach yields a wealth of both energetic and structural information at minimal computational cost.     

Preparation and characterization of pi-stacking quinodimethane oligothiophenes. Predicting semiconductor behavior and bandwidths from crystal structures and molecular orbital calculations

A series of new quinodimethane-substituted terthiophene and quaterthiophene oligomers has been investigated for comparison with a previously studied quinoid oligothiophene that has demonstrated high mobilities and ambipolar transport behavior in thin-film transistor devices. Each new quinoidal thiophene derivative shows a reversible one-electron oxidation between 0.85 and 1.32 V, a quasi-reversible one-electron second oxidation between 1.37 and 1.96 V, and a reversible two-electron reduction between -0.05 and -0.23 V. The solution UV-vis-NIR spectrum of each compound is dominated by an intense (epsilon congruent with 100 000 M(-1) cm(-1)) low energy pi-pi transition that has a lambda(max) ranging between 648 and 790 nm. All X-ray crystal structures exhibit very planar quinoidal backbones and short intermolecular pi-stacking distances (3.335-3.492 A). Structures exhibit a single pi-stacking distance with parallel cofacial stacking (sulfur atoms of equivalent rings pointed in the same direction) or with alternating distances and antiparallel cofacial stacking (sulfur atoms of equivalent rings pointed in the opposite direction). Examples of the layered and herringbone-packing motifs are observed for both the parallel and the antiparallel cofacial stacking. Analysis of the X-ray structures and molecular orbital calculations indicates that all of these compounds have one-dimensional electronic band structures as a result of the pi-stacking. For structures with a unique pi-stacking distance, a simple geometric overlap parameter calculated from the shape of the molecule and the slip from perfect registry in the pi-stack correlates well with the transfer integrals (t) calculated using molecular orbital theory. The calculated valence (633 meV) and conduction (834 meV) bandwidths for a quinoid quaterthiophene structure are similar to those calculated for the benchmark pentacene and indicate that both hole and electron mobilities could be significant.     

(10,3)-a Noninterpenetrated network built from a Piedfort ligand pair

The Friedel-Crafts reaction of cyameluric chloride with toluene and subsequent oxidation have resulted in the synthesis of a benzoic acid functionalized tri-s-triazine derivative, s-heptazine tribenzoate (HTB). Photoluminescence and mass spectroscopy data indicate that, in solution, HTB molecules interact by face-to-face pi-pi stacking, forming dimers (the "Piedfort unit"). A porous metal-organic framework (MOF) with a (10,3)-a chiral network has been synthesized with these dimers at the three-connected nodes linking trinuclear zinc clusters. Within the network, the dimer can exist in either of two enantiomeric forms because of an angular offset in the stacking. The resulting MOF is neutral and noninterpenetrated and exhibits a high solvent-accessible volume (calculated 84%).     

Separation and online preconcentration by multistep stacking with large-volume injection of anabolic steroids by capillary electrokinetic chromatography using charged cyclodextrins and UV-absorption detection

The separation of three common anabolic steroids (methyltestosterone, methandrostenolone and testosterone) was performed for the first time by capillary EKC. Different charged CD derivatives and bile salts were tested as dispersed phases in order to achieve the separation. A mixture of 10 mmol/L succinylated-beta-CD with 1 mmol/L beta-CD in a 50 mmol/L borate buffer (pH 9) enabled the separation of the three anabolic steroids in less than 9 min. Concentration LODs, obtained for these compounds with low absorption of UV light, were approximately 5 x 10(-5) mol/L. The use of online reverse migrating sample stacking with large-volume injection (the effective length of the capillary) enabled to improve the detection sensitivity. Sensitivity enhancement factors (SEFs) ranging from 95 (for testosterone) to 149 (for methyltestosterone) were achieved by single stacking preconcentration. Then, the possibilities of multistep stacking to improve the sensitivity for these analytes were investigated. SEFs obtained by double stacking preconcentration ranged from 138 to 185, enabling concentration LODs of 2.79 x 10(-7) mol/L (for methyltestosterone), 3.47 x 10(-7) mol/L (for testosterone) and 3.56 x 10(-7) mol/L (for methandrostenolone). Although online triple stacking preconcentration was achieved, its repeatability was very poor and SEFs for the studied analytes were not calculated.     

SCF CI MO calculations on the base–base interactions in dinucleoside monophosphates

In order to elucidate further details of RNA conformations we have studied base stacking in dinucleoside monophosphates (DNP's) using UV difference spectra and the hypochromic effect. SCF CI MO calculations according to PPP and MIM approximations were carried out for six pyrimidine-containing DNP's in each of several stacking geometries. The calculated and plotted difference spectra were fitted to the experimental spectra. Different DNP's showed distinct geometries in the range of the helix angle of 35°. From our results we conclude that there is a microstructure in the helix. This would imply an additional content of information in this macromolecule, a higher precision in nucleic acid interactions, and make possible the prediction of the conformation of polynucleotides.     

Analysis of stacking overlap in nucleic acid structures: algorithm and application

RNA contains different secondary structural motifs like pseudo-helices, hairpin loops, internal loops, etc. in addition to anti-parallel double helices and random coils. The secondary structures are mainly stabilized by base-pairing and stacking interactions between the planar aromatic bases. The hydrogen bonding strength and geometries of base pairs are characterized by six intra-base pair parameters. Similarly, stacking can be represented by six local doublet parameters. These dinucleotide step parameters can describe the quality of stacking between Watson–Crick base pairs very effectively. However, it is quite difficult to understand the stacking pattern for dinucleotides consisting of non canonical base pairs from these parameters. Stacking interaction is a manifestation of the interaction between two aromatic bases or base pairs and thus can be estimated best by the overlap area between the planar aromatic moieties. We have calculated base pair overlap between two consecutive base pairs as the buried van der Waals surface between them. In general, overlap values show normal distribution for the Watson–Crick base pairs in most double helices within a range from 45 to 50 Å² irrespective of base sequence. The dinucleotide steps with non-canonical base pairs also are seen to have high overlap value, although their twist and few other parameters are rather unusual. We have analyzed hairpin loops of different length, bulges within double helical structures and pseudo-continuous helices using our algorithm. The overlap area analyses indicate good stacking between few looped out bases especially in GNRA tetraloop, which was difficult to quantitatively characterise from analysis of the base pair or dinucleotide step parameters. This parameter is also seen to be capable to distinguish pseudo-continuous helices from kinked helix junctions.     

Stacking of Metal Chelates with Benzene: Can Dispersion‐Corrected DFT Be Used to Calculate Organic–Inorganic Stacking?

CCSD(T)/CBS energies for stacking of nickel and copper chelates are calculated and used as benchmark data for evaluating the performance of dispersion‐corrected density functionals for calculating the interaction energies. The best functionals for modeling the stacking of benzene with the nickel chelate are M06HF‐D3 with the def2‐TZVP basis set, and B3LYP‐D3 with either def2‐TZVP or aug‐cc‐pVDZ basis set, whereas for copper chelate the PBE0‐D3 with def2‐TZVP basis set yielded the best results. M06L‐D3 with aug‐cc‐pVDZ gives satisfying results for both chelates. Most of the tested dispersion‐corrected density functionals do not reproduce the benchmark data for stacking of benzene with both nickel (no unpaired electrons) and copper chelate (one unpaired electron), whereas a number of these functionals perform well for interactions of organic molecules.     

A structure with an irregular layer lattice in poly(γ-methyl L-glutamate-co-γ-benzyl L-glutamate) film

Two types of films showing different characteristic x-ray equatorial patterns were prepared from chloroform and N,N-dimethylformamide solutions of poly(γ-methyl L -glutamate-co-γ-benzyl L -glutamate). In the film cast from chloroform solution, the x-ray pattern on the equator consisted of a remarkable mixture of sharp and diffuse reflections, with the sharp reflections corresponding to integral values of 1/3k. On the other hand, in the film cast from N,N-dimethylformamide solution, a well-defined x-ray pattern was observed. An explanation for this characteristic pattern of chloroform-cast film was made on the basis of a structural model wherein stacking faults or dislocations are incorporated into the ordered structure characteristic of N,N-dimethylformamide-cast film. Two domains divided by a stacking fault are mutually displaced along the (100) crystal planes, but the shape and size of the unit cell is everywhere the same. The intensity distribution of x-ray diffraction was calculated as a function of the probability of a stacking fault occurring in a regular sequence of (100) planes. The best correspondence with observation was obtained with a stacking fault in every three layers, on the average.     

Stacking of Benzene with Metal Chelates: Calculated CCSD(T)/CBS Interaction Energies and Potential‐Energy Curves

Accurate values for the energies of stacking interactions of nickel‐ and copper‐based six‐membered chelate rings with benzene are calculated at the CCSD(T)/CBS level. The results show that calculations made at the ωB97xD/def2‐TZVP level are in excellent agreement with CCSD(T)/CBS values. The energies of [Cu(C₃H₃O₂)(HCO₂)] and [Ni(C₃H₃O₂)(HCO₂)] chelates stacking with benzene are ?6.39 and ?4.77 kcal mol^?1, respectively. Understanding these interactions might be important for materials with properties that are dependent on stacking interactions.     

Effect of stacking and redox state on optical absorption spectra of melanins -- comparison of theoretical and experimental results

In this work the effect of aggregation and oxidation on the optical absorption of eumelanin oligomeric sheets is investigated by applying quantum mechanics and atomistic simulation studies to a simplified eumelanin structural model that includes 1-3 sheets of hexameric oligomer sheets. The oligomeric hypothesis is supported by AFM characterizations of synthetic eumelanins, formed by auto-oxidation or electrochemical oxidation of dihydroxyindole (DHI). Comparison of calculated absorption spectra to experimental spectra demonstrates a red shift in absorption with oxidation and stacking of the eumelanin and validates the theoretical results.     

A quantum chemistry study of binding carotenoids in the bacterial light-harvesting complexes

Carotenoids play the dual function of light harvesting and photoprotection in photosynthetic organisms. Despite their functional importance, the molecular basis for binding of carotenoids in the photosynthetic proteins is poorly understood. We have discovered that all carotenoids are surrounded either by aromatic residues or by chlorophylls in all known crystal structures of the photosynthetic pigment-protein complexes. The intermolecular pi-pi stacking interactions between carotenoids and the surrounding aromatic residues in the light-harvesting complex II (LH-II) of Rhodospirillum molischianum were analyzed by high level ab initio electronic structure calculations. Intermolecular interaction energies were calculated with the second-order M?ller-Plesset perturbation method (MP2) using the modified 6-31G*(0.25) basis set with diffuse d-polarization by Hobza and co-workers. The MP2/6-31G*(0.25) calculations yield a total stabilization energy of -15.66 kcal/mol between the carotenoid molecule and the four surrounding aromatic residues (alpha-Trp-23, beta-Phe-20, beta-Phe-24, beta-Phe-27). It is thus concluded that pi-pi stacking interactions between carotenoids and the aromatic residues play an essential role in binding carotenoids in the LH-II complex of Rhodospirillum molischianum. The physical nature of the pi-pi stacking interactions was further analyzed, and the dispersion interactions were found to be the dominant intermolecular attraction force. There is also a substantial electrostatic contribution to the overall intermolecular stabilization energy.