Anchoring the potential energy surface of the cyclic water trimer

Six cyclic stationary points on the water trimer potential energy surface have been fully optimized at the MP2 level with the aug-cc-pVQZ basis set. In agreement with previous work, harmonic vibrational frequencies indicate that two structures are minima, three are transition states connecting minima on the surface while the remaining stationary point is a higher-order saddle point. The 1- and n-particle limits of the electronic energies of each of these six structures were estimated by systematically varying both the basis sets and theoretical methods. The former limit was approached with the cc-pVXZ and aug-cc-pVXZ families of basis sets (X=2-7) while MP2, CCSD(T), and BD(TQ) calculations helped examine the latter. Core correlation effects have also been assessed at the MP2 level with the cc-pCVXZ series of basis sets (X=2-5). These data have been combined to provide highly accurate relative energies and dissociation energies for these stationary points.     

DNA甲基化-非甲基化碱基间堆积作用的理论研究

运用二级Mфller-Plesset(MP2)理论方法和cc-pVDZ基组优化了6-甲基鸟嘌呤(O6-MethylG),4-甲基胸腺嘧啶(O4-MethylT)以及5-甲基胞嘧啶(C5-MethylC)与DNA碱基鸟嘌呤(G),腺嘌呤(A),胞嘧啶(C),胸腺嘧啶(T)之间的堆积构型.在MP2/aug-cc-pVXZ//MP2/cc-pVDZ(X=D,T)水平上,采用完全基组外推方法校正了堆积碱基对间的相互作用能,并用完全均衡校正法(CP)校正了基组重叠误差(BSSE).MP2计算结果表明,DNA碱基甲基化使得嘧啶-嘧啶、嘧啶-嘌呤堆积碱基间的平行旋转角发生明显改变,并使堆积碱基间的相互作用能增大.在MP2/cc-pVDZ计算级别上得到了各堆积碱基对的全电子波函数,并用分子中的原子理论(AIM)分析了堆积碱基对间的弱相互作用.AIM分析结果显示,甲基化增强了堆积碱基间的π-π作用,且甲基氢与相邻碱基间形成H2CH…X(X=O,N,CH3,NH2)等类型的氢键.甲基化损伤使碱基间重叠程度增大、π-π作用增强以及堆积碱基间形成多个氢键,是堆积作用能增加的主要原因.     

TDDFT investigation on nucleic acid bases: comparison with experiments and standard approach

A comprehensive theoretical study of electronic transitions of canonical nucleic acid bases, namely guanine, adenine, cytosine, uracil, and thymine, was performed. Ground state geometries were optimized at the MP2/6-311G(d,p) level. The nature of respective potential energy surfaces was determined using the harmonic vibrational frequency analysis. The MP2 optimized geometries were used to compute electronic vertical singlet transition energies at the time-dependent density functional theory (TDDFT) level using the B3LYP functional. The 6-311++G(d,p), 6-311(2+,2+)G(d,p), 6-311(3+,3+)G(df,pd), and 6-311(5+,5+)G(df,pd) basis sets were used for the transition energy calculations. Computed transition energies were found in good agreement with the corresponding experimental data. However, in higher transitions, the Rydberg contaminations were also obtained. The existence of pisigma* type Rydberg transition was found near the lowest singlet pipi* state of all bases, which may be responsible for the ultrafast deactivation process in nucleic acid bases.     

Estimated MP2 and CCSD(T) interaction energies of n-alkane dimers at the basis set limit: comparison of the methods of Helgaker et al. and Feller

The MP2 (the second-order M?ller-Plesset calculation) and CCSD(T) (coupled cluster calculation with single and double substitutions with noniterative triple excitations) interaction energies of all-trans n-alkane dimers were calculated using Dunning's [J. Chem. Phys. 90, 1007 (1989)] correlation consistent basis sets. The estimated MP2 interaction energies of methane, ethane, and propane dimers at the basis set limit [EMP2(limit)] by the method of Helgaker et al. [J. Chem. Phys. 106, 9639 (1997)] from the MP2/aug-cc-pVXZ (X=D and T) level interaction energies are very close to those estimated from the MP2/aug-cc-pVXZ (X=T and Q) level interaction energies. The estimated EMP2(limit) values of n-butane to n-heptane dimers from the MP2/cc-pVXZ (X=D and T) level interaction energies are very close to those from the MP2/aug-cc-pVXZ (X=D and T) ones. The EMP2(limit) values estimated by Feller's [J. Chem. Phys. 96, 6104 (1992)] method from the MP2/cc-pVXZ (X=D, T, and Q) level interaction energies are close to those estimated by the method of Helgaker et al. from the MP2/cc-pVXZ (X=T and Q) ones. The estimated EMP2(limit) values by the method of Helgaker et al. using the aug-cc-pVXZ (X=D and T) are close to these values. The estimated EMP2(limit) of the methane, ethane, propane, n-butane, n-pentane, n-hexane, n-heptane, n-octane, n-nonane, and n-decane dimers by the method of Helgaker et al. are -0.48, -1.35, -2.08, -2.97, -3.92, -4.91, -5.96, -6.68, -7.75, and -8.75 kcal/mol, respectively. Effects of electron correlation beyond MP2 are not large. The estimated CCSD(T) interaction energies of the methane, ethane, propane, and n-butane dimers at the basis set limit by the method of Helgaker et al. (-0.41, -1.22, -1.87, and -2.74 kcal/mol, respectively) from the CCSD(T)/cc-pVXZ (X=D and T) level interaction energies are close to the EMP2(limit) obtained using the same basis sets. The estimated EMP2(limit) values of the ten dimers were fitted to the form m0+m1X (X is 1 for methane, 2 for ethane, etc.). The obtained m0 and m1 (0.595 and -0.926 kcal/mol) show that the interactions between long n-alkane chains are significant. Analysis of basis set effects shows that cc-pVXZ (X=T, Q, or 5), aug-cc-pVXZ (X=D, T, Q, or 5) basis set, or 6-311G** basis set augmented with diffuse polarization function is necessary for quantitative evaluation of the interaction energies between n-alkane chains.     

The effect of methylation on the hydrogen-bonding and stacking interaction of nucleic acid bases

Methylated nucleosides play an important role in DNA/RNA function, and may affect republication by interrupting the base-pairing and base-stacking. In order to investigate the effect of methylation on the interaction between nucleic acid bases, this work presents the hydrogen-bonding and stacking interactions between 5-methylcytosine and guanine (G), cytosine (C) and G, 1-methyladenine and thymine (T), as well as adenine and T. Geometry optimization and potential energy surface scan have been performed for the involved complexes by MP2 calculations. The interaction energies, which were corrected for the basis-set superposition error by the full Boys–Bernardi counterpoise correction scheme, were used to evaluate the interaction intensity of these nucleic acid bases. The atoms in molecules theory and natural bond orbital analysis have been performed to study the hydrogen bonds in these complexes. The result shows that the methyl substitute contributes the stability to these complexes because it enhances either the hydrogen bonding or the staking interaction between nucleic acid bases studied.     

Comprehensive study of the effects of methylation on tautomeric equilibria of nucleic acid bases

Minor tautomers of nucleic acid bases can result by intramolecular proton transfer. These rare tautomers could be stabilized through the addition of methyl groups to DNA bases. A comprehensive theoretical study of tautomers of methylated derivatives of guanine, adenine, cytosine, thymine, and uracil was performed. Molecular geometries of all tautomers were obtained at the density functional theory and MP2 levels with the 6-31G(d,p) basis set, and single-point calculations were performed at the CCSD(T)/6-311G(d,p) level. Tautomers obtained by protonation at the preferred protonation site for methylated isolated bases were compared to their nonmethylated counterparts. The effects of methylation on the relative stabilities of nucleic acid base tautomers are also studied and discussed in this work. The results suggest that some sites on the bases may not be mutagenic and may even stabilize the canonical Watson-Crick form. The results also indicate that a number of methylation sites can stabilize the tautomers, suggesting possible mechanisms for mutagenic changes.     

On the relative acidity and basicity of the amino groups of the nucleic acid bases

Quantum chemical calculations are reported on the deprotonation and protonation of the amino groups of the nucleic acid bases adenine, guanine and cytosine, in an attempt to compare the relative reactivities of these groups. In the light of renewed interest in the amino groups as reactive sites for certain carcinogenic and carcinostatic agents, we discuss the possible significance of our results for the interpretation of these molecular interactions.     

Are isolated nucleic acid bases really planar? A Car-Parrinello molecular dynamics study

Car-Parrinello molecular dynamics simulations of the flexibility of isolated DNA bases have been carried out. The comparison of lowest ring out-of-plane vibrations calculated by using MP2/cc-pvdz and BLYP/PW methods reveals that the DFT method with the plane wave basis set reasonably reproduces out-of-plane deformability of the pyrimidine ring in nucleic acid bases and could be used for reliable modeling of conformational flexibility of nucleobases. The conformational phase space of pyrimidine rings in thymine, cytosine, guanine, and adenine has been investigated by using the ab initio Car-Parrinello molecular dynamics method. It is demonstrated that all nucleic acid bases are highly flexible molecules and possess a nonplanar effective conformation of the pyrimidine ring despite the fact that the planar geometry corresponds to a minimum on the potential energy surface. The population of the planar geometry of the pyrimidine ring does not exceed 30%. Among the nonplanar conformations of the pyrimidine rings, the boat-like and half-chair conformations are the most populated.     

DNA-conducting polymer complexes: a computational study of the hydrogen bond between building blocks

Ab initio quantum mechanical calculations at the MP2 level were used for an extensive study concerning the stability of hydrogen-bonded complexes formed by pyrrole and thiophene, which are the most common building blocks of conducting polymers, and DNA bases. Results indicated that very stable complexes were formed with pyrrole, which shows a clear tendency to form specific hydrogen-bonding interactions with nucleic acid bases. Furthermore, the strength of such interactions depends significantly on the base, growing in the following order: thymine < adenine approximately equal to cytosine < guanine. On the contrary, thiophene formed complexes stabilized by nonspecific interactions between the pi-cloud of the ring and the N-H groups of the nucleic acid bases rather than specific hydrogen bonds. Overall, these results are fully consistent with experimental observations: polypyrrole is able not only to stabilize adducts with DNA but also to interact specifically, while the interactions of the latter with polythiophene and their derivatives are weaker and nonspecific.     

Structural and electronic property changes of the nucleic acid bases upon base pair formation

A systematic study of structures and electronic properties has been carried out for the nucleic acid bases adenine, guanine, thymine, and cytosine and for the base pairs adenine–thymine and guanine–cytosine. We focus our attention on these properties, which experience significant changes when single nucleic bases join to form base pairs. Such properties are expected to play an important role during the formation of the DNA molecule in its B conformation. All-electron calculations with inclusion of correlation effects were performed according to the local and nonlocal density functional approaches. We compare our results with previous ab initio and semiempirical values and with available experimental data. Advantages and disadvantages for these density functional-based methods are discussed. We conclude that applications of such models to investigate larger compounds of a similar nature are promising. © 1994 by John Wiley & Sons, Inc.     

At nonzero temperatures, stacked structures of methylated nucleic acid base pairs and microhydrated nonmethylated nucleic acid base pairs are favored over planar hydrogen-bonded structures: a molecular dynamics simulations study

The dynamic structure of all ten possible nucleic acid (NA) base pairs and methylated NA base pairs hydrated by a small number of water molecules (from 1 to 16) was determined by using molecular dynamics simulations in the NVE microcanonical and NVT canonical ensembles with the Cornell force field (W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. E. Caldwell, P. Kollman, J. Am. Chem. Soc. 1995, 117, 5179). The presence of one water molecule does not affect the structure of any hydrogen-bonded (H-bonded) nonmethylated base pair. An equal population of H-bonded and stacked structures of adenine...adenine, adenine...guanine and adenine... thymine pairs is reached if as few as two water molecules are present, while obtaining equal populations of these structures in the case of adenine...cytosine, cytosine...thymine, guanine... guanine and guanine...thymine required the presence of four water molecules, and in the case of guanine...cytosine, six. A comparable population of planar, H-bonded and stacked structures for cytosine...cytosine and thymine... thymine base pairs was only obtained if at least eight water molecules hydrated a pair. Methylation of bases changed the situation dramatically and stacked structures were favoured over H-bonded ones even in the absence of water molecules in most cases. Only in the case of methyl cytosine...methyl cytosine, methyl guanine...methyl guanine and methyl guanine...methyl cytosine pairs were two, two or six water molecules, respectively, needed in order to obtain a comparable population of planar, H-bonded and stacked structures. We believe that these results give clear evidence that the preferred stacked structure of NA base pairs in the microhydrated environment, and also apparently in a regular solvent, is due to the hydrophilic interaction of a small number of water molecules. In the case of methylated bases, it is also due to the fact that the hydrogen atoms most suitable for the formation of H-bonds have been replaced by a methyl group. A preferred stacked structure is, thus, not due to a hydrophobic interaction between a large bulk of water molecules and the base pair, as believed.     

Natural resonance structures and aromaticity of the nucleobases

Natural resonance theory (NRT) and nucleus- independent chemical shift (NICS) analyses have been applied to the standard nucleobases adenine, guanine, cytosine, uracil, and thymine. The molecular electron densities were obtained from density functional theory calculations at the B3LYP level and ab initio calculations at the HF, MP2, and CCD levels. Compared with the dominance of the two Kekulé structures in benzene, the structural modifications in the forms of endocyclic heteroatoms and exocyclic substituents introduce various degrees of charge separation in nucleobases. As a result, the leading resonance structures for cytosine, uracil, and thymine are found to be covalent structures, but their weightings decrease to ~30% in the NRT expansion. For adenine and guanine, the covalent structures have weightings of ~20%, and the leading ionic resonance structures have weightings of as high as about 8%. Methods that include electron correlation effects, B3LYP, MP2, and CCD, give smaller weightings for the covalent structures than HF. However, MP2 and CCD results often include “strange” resonance structures with connections between unbonded vicinal atoms, making DFT at the B3LYP level the better choice for calculating these molecules’ electron density. The NICS at the ring center shows that the six-membered rings in cytosine, uracil, thymine, and guanine are nonaromatic with NICS within − 3 to − 1 ppm, while it is − 7.3 ppm for the six-membered ring in adenine. The NICS of the five-membered rings of adenine and guanine is around − 12 ppm, a slight decrease from the value of − 15.0 ppm for pyrrole.     

Conformational flexibility of pyrimidine rings of nucleic acid bases in polar environment: PCM study

The results of calculations of molecular structures of nucleic acid bases in polar environment using Polarized Continuum Model of solvent combined with the MP2/cc-pvdz level of ab initio theory demonstrate considerable polarization of thymine, cytosine, and guanine. This phenomenon can be related to considerable contribution of zwitter-ionic resonant forms into total structure of the studied species. It leads to significant increase (about 30%) of frequencies of the out-of-plane pyrimidine ring vibrations and is related to considerable decrease of conformational flexibility of heterocycle due to smaller out-of-plane deformability of pyrimidine ring in zwitter-ionic resonant forms. In the case of adenine, the presence of a polar environment results in an increase of conformational flexibility of pyrimidine ring.     

AN EXTENDED SEMI-EMPIRICAL MOLECULAR ORBITAL STUDY OF THE * EXCITED STATES OF NUCLEIC ACID BASES

Spectroscopic CNDO/S and INDO/S calculations of the * spectra of the nucleic acid bases uracil, cytosine, adenine and guanine were performed. Oscillator strengths, polarizations and transition densities are displayed for transitions to 140 nm using several parameter sets and demonstrating the effect of doubly excited configurations. Inclusion of near-neighbor off-diagonal transition density elements greatly assists in making state correlations and assignments. Interesting effects regarding electron repulsion parameterization are noted. The results are compared with recently reported experimental results and several serious points of disagreement are noted.     

核酸水解产物嘌呤、嘧啶碱基在BDS柱上的分离及测定

 用高效液相色谱法测定了核酸水解的中间产物及最终产物 6种嘌呤、嘧啶碱基 ,探讨了色谱柱、流动相等对其分离的影响 ,确定了最佳色谱条件为 :HypersilBDS C18柱 ,乙腈 0 1mol/LKH2 PO4 (H3 PO4 调节 pH至4 0 5 ) (体积比为 2∶98)作流动相 ,紫外检测器在 2 6 0nm波长下检测。方法的精密度在 3%以内 ,回收率在 82 %～ 114%。方法应用于酵母核酸样品的测定中 ,取得了很好的结果。     

A quantum chemical study of reactions of DNA bases with sulphur mustard: a chemical warfare agent

Reactions of the sulphonium ion of sulphur mustard (SM⁺¹) at the N7, N3 and O6 sites of guanine, N7, N3 and N1 sites of adenine, O2 and N3 sites of cytosine and O2 and O4 sites of thymine were studied theoretically in gas phase and aqueous media employing density functional theory (DFT) and second order Møller–Plesset perturbation (MP2) theory. The B3LYP, B3PW91 and B1B95 functionals of DFT and the 6-31+G* and AUG-cc-pVDZ basis sets were used in the calculations. Basis set superposition error was treated using the counterpoise method by single point energy calculations at the B3LYP/6-31+G* level in gas phase. The present study explains the mechanism of alkylation of the DNA bases and shows that SM⁺¹ would form stable adducts at the endocyclic nitrogen sites of the DNA bases, and at the O6 site of guanine and the O2 site of cytosine. Formation of adducts at the N7 site of guanine and N3 site of adenine are found to be most favored and next most favored respectively, which agrees with experimental observations.     

Toward true DNA base-stacking energies: MP2, CCSD(T), and complete basis set calculations

Stacking energies in low-energy geometries of pyrimidine, uracil, cytosine, and guanine homodimers were determined by the MP2 and CCSD(T) calculations utilizing a wide range of split-valence, correlation-consistent, and bond-functions basis sets. Complete basis set MP2 (CBS MP2) stacking energies extrapolated using aug-cc-pVXZ (X = D, T, and for pyrimidine dimer Q) basis sets equal to -5.3, -12.3, and -11.2 kcal/mol for the first three dimers, respectively. Higher-order correlation corrections estimated as the difference between MP2 and CCSD(T) stacking energies amount to 2.0, 0.7, and 0.9 kcal/mol and lead to final estimates of the genuine stacking energies for the three dimers of -3.4, -11.6, and -10.4 kcal/mol. The CBS MP2 stacking-energy estimate for guanine dimer (-14.8 kcal/mol) was based on the 6-31G(0.25) and aug-cc-pVDZ calculations. This simplified extrapolation can be routinely used with a meaningful accuracy around 1 kcal/mol for large aromatic stacking clusters. The final estimate of the guanine stacking energy after the CCSD(T) correction amounts to -12.9 kcal/mol. The MP2/6-31G(0.25) method previously used as the standard level to calculate aromatic stacking in hundreds of geometries of nucleobase dimers systematically underestimates the base stacking by ca. 1.0-2.5 kcal/mol per stacked dimer, covering 75-90% of the intermolecular correlation stabilization. We suggest that this correction is to be considered in calibration of force fields and other cheaper computational methods. The quality of the MP2/6-31G(0.25) predictions is nevertheless considerably better than suggested on the basis of monomer polarizability calculations. Fast and very accurate estimates of the MP2 aromatic stacking energies can be achieved using the RI-MP2 method. The CBS MP2 calculations and the CCSD(T) correction, when taken together, bring only marginal changes to the relative stability of H-bonded and stacked base pairs, with a slight shift of ca. 1 kcal/mol in favor of H-bonding. We suggest that the present values are very close to ultimate predictions of the strength of aromatic base stacking of DNA and RNA bases.     

Stacking of the mutagenic DNA base analog 5-bromouracil

The potential energy surface of the stacked 5-bromouracil/uracil (BrU/U) dimer has been investigated in the gas phase and in solution (water and 1,4-dioxane), modeled by a continuum solvent using the polarizable continuum model. Minima and transition states were optimized using DFT (the M06-2X density functional and the 6-31+G(d) basis set). Six stacked gas-phase BrU/U minima were located: four in the face-to-back orientation and two face-to-face. The global minimum in the gas phase is a face-to-face structure with a twist angle of 60° and a zero-point energy-corrected interaction energy of ?10.7 kcal/mol. The BrU/U potential energy surface is geometrically and energetically similar to that of U/U (Hunter and Van Mourik in J Comput Chem 33:2161, 2012). Energy calculations were also performed on experimental geometries of stacked dimers (47 containing BrU stacking with either adenine, cytosine, guanine or thymine and 51 containing thymine also stacking with one of those four bases) taken from DNA structures in the Protein Data Bank. Single-point interaction energies were computed at different levels of theory including MP2, CCSD(T) and DFT using the mPW2PLYP-D double-hybrid functional augmented with an empirical dispersion term, using basis sets ranging from aug-cc-pVDZ to aug-cc-pVQZ. No strong evidence was found for the suggestion that the mutagenicity of BrU is due to enhanced stacking of BrU compared to the corresponding stacked dimers involving thymine.     

True stabilization energies for the optimal planar hydrogen-bonded and stacked structures of guanine...cytosine, adenine...thymine, and their 9- and 1-methyl derivatives: complete basis set calculations at the MP2 and CCSD(T) levels and comparison with experiment

Planar H-bonded and stacked structures of guanine...cytosine (G.C), adenine...thymine (A...T), 9-methylguanine...1-methylcytosine (mG...mC), and 9-methyladenine...1-methylthymine (mA...mT) were optimized at the RI-MP2 level using the TZVPP ([5s3p2d1f/3s2p1d]) basis set. Planar H-bonded structures of G...C, mG...mC, and A...T correspond to the Watson-Crick (WC) arrangement, in contrast to mA...mT for which the Hoogsteen (H) structure is found. Stabilization energies for all structures were determined as the sum of the complete basis set limit of MP2 energies and a (DeltaE(CCSD(T)) - DeltaE(MP2)) correction term evaluated with the cc-pVDZ(0.25,0.15) basis set. The complete basis set limit of MP2 energies was determined by two-point extrapolation using the aug-cc-pVXZ basis sets for X = D and T and X = T and Q. This procedure is required since the convergency of the MP2 interaction energy for the present complexes is rather slow, and it is thus important to include the extrapolation to the complete basis set limit. For the MP2/aug-cc-pVQZ level of theory, stabilization energies for all complexes studied are already very close to the complete basis set limit. The much cheaper D-->T extrapolation provided a complete basis set limit close (by less than 0.7 kcal/mol) to the more accurate T-->Q term, and the D-->T extrapolation can be recommended for evaluation of complete basis set limits of more extended complexes (e.g. larger motifs of DNA). The convergency of the (DeltaE(CCSD(T)) - DeltaE(MP2)) term is known to be faster than that of the MP2 or CCSD(T) correlation energy itself, and the cc-pVDZ(0.25,0.15) basis set provides reasonable values for planar H-bonded as well as stacked structures. Inclusion of the CCSD(T) correction is essential for obtaining reliable relative values for planar H-bonding and stacking interactions; neglecting the CCSD(T) correction results in very considerable errors between 2.5 and 3.4 kcal/mol. Final stabilization energies (kcal/mol) for the base pairs studied are very substantial (A...T WC, 15.4; mA...mT H, 16.3; A...T stacked, 11.6; mA...mT stacked, 13.1; G...C WC, 28.8; mG...mC WC, 28.5; G...C stacked, 16.9; mG...mC stacked, 18.0), much larger than published previously. On the basis of comparison with experimental data, we conclude that our values represent the lower boundary of the true stabilization energies. On the basis of error analysis, we expect the present H-bonding energies to be fairly close to the true values, while stacked energies are still expected to be about 10% too low. The stacking energy for the mG...mC pair is considerably lower than the respective H-bonding energy, but it is larger than the mA...mT H-bonding energy. This conclusion could significantly change the present view on the importance of specific H-bonding interactions and nonspecific stacking interactions in nature, for instance, in DNA. Present stabilization energies for H-bonding and stacking energies represent the most accurate and reliable values and can be considered as new reference data.