精氨酸侧链和核酸碱基间离子氢键作用强度分析

采用MP2/6-31+G(d,p)方法优化得到了22个由精氨酸侧链与碱基尿嘧啶、 胸腺嘧啶、 胞嘧啶、 鸟嘌呤及腺嘌呤形成的氢键复合物的气相稳定结构, 使用包含BSSE校正的MP2/aug-cc-pVTZ方法计算得到了复合物的气相结合能, 通过MP2/6-31+G(d,p)方法和PCM模型优化得到了复合物的水相稳定结构, 采用MP2/aug-cc-pVTZ方法和PCM模型计算得到了复合物的水相结合能. 研究发现, 精氨酸侧链与碱基间的离子氢键作用强度与单体间电荷转移量、 氢键临界点电子密度及二阶作用稳定化能密切相关. 与中性氢键相比, 离子氢键作用具有更显著的共价作用成分. 研究还发现, 精氨酸侧链和碱基间形成的氢键复合物的稳定性次序可以通过氢键受体碱基分子上氧原子和氮原子的质子化反应焓变进行预测, 质子化反应焓变越负, 形成的氢键复合物越稳定.     

6-烷基鸟嘌呤与DNA碱基间氢键作用的理论研究

用密度泛函B3LYP方法在6-311＋G**基组水平上对鸟嘌呤及顺(cis-)、反式(anti-)-6-烷基鸟嘌呤(O⁶-AlkylG)与DNA碱基(胸腺嘧啶T、胞嘧啶C、腺嘌呤A、鸟嘌呤G)的氢键二聚体结构进行了优化. 在MP2/cc-pVXZ(X＝D,T)// B3LYP/6-311＋G**水平上, 采用完全基组外推方法校正了氢键二聚体的相互作用能, 并用完全均衡校正法(CP)校正了基组重叠误差(BSSE). 在B3LYP/6-311＋G**水平上计算了各氢键碱基对的全电子波函数, 并用分子中的原子理论(AIM)分析了碱基间的弱相互作用. 计算结果显示, 鸟嘌呤6-O烷基化改变了碱基间的氢键作用模式, 使碱基对发生了明显的螺旋桨式扭转和不同程度的位移, 碱基间的电子密度分布和氢键作用能明显减小. O⁶-AlkylG对DNA碱基间的氢键作用是去稳定化的, 去稳定化影响的顺序为GC＞GG＞GA≈GT. 计算结果与文献给出的实验结论基本一致.     

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.     

核酸碱基与甘氨酸二肽间氢键作用的最佳位点

优化得到了碱基腺嘌呤、胸腺嘧啶、尿嘧啶、鸟嘌呤及胞嘧啶与甘氨酸二肽分子形成的28个氢键复合物的稳定结构并计算了结合能, 探讨了五种碱基与甘氨酸二肽分子间氢键作用的最佳位点. 本文研究发现: 每种碱基均可以通过不同位点与二肽分子形成氢键复合物, 腺嘌呤、胸腺嘧啶、尿嘧啶、鸟嘌呤及胞嘧啶分别最倾向使用A3、T1、U1、G3及C1位点与甘氨酸二肽分子形成氢键复合物; 碱基分子某位点的质子化反应焓变越负所形成的氢键复合物越稳定, 去质子化反应焓变越小所形成的氢键复合物越稳定; 由氢键复合物的结合能计算得到的稳定性次序与由碱基分子质子化和去质子化反应焓变推得的稳定性次序一致.     

水溶液中氨基酸侧链对G∶C碱基对间氢键影响的理论研究

利用量子化学方法研究了气相和水溶液下,氨基酸侧链与鸟嘌呤和胞嘧啶间的氢键作用.应用B3LYP/6-31+G(d,p)方法优化复合物几何结构,使用MP2/aug-cc-p VDZ方法进行复合物能量、自然键轨道(NBO)电荷和二阶稳定化能的计算.结果表明,水溶液可使氨基酸侧链与碱基或碱基对之间氢键键能显著减小;带电复合物气相和水溶液氢键键能之差范围为50.63~146.48 k J/mol,中性为0.17~24.94 k J/mol;电荷的转移量与氢键键能成正比,电荷转移量越多,复合物越稳定;二阶稳定化能与氢键键长成反比,与电荷转移量成正比,且气相与水溶液氢键二阶稳定化能之比约为两相的电荷转移量之比.水溶液对该类体系中氢键作用具有明显影响.     

儿茶素-胞嘧啶分子间相互作用的密度泛函研究

采用密度泛函理论的B3LYP方法,在6-31+G*基组水平上研究了儿茶素-胞嘧啶分子间相互作用机制,得到稳定的儿茶素-胞嘧啶复合物11个.计算结果表明氢键对于复合物的稳定性起着重要的作用,并且当复合物形成2个或更多的氢键时,氢键的类型及强度共同决定着复合物的稳定性.我们还应用了分子中的原子(AIM)理论和自然键轨道(NBO)理论对这11种复合物中氢键的性质和特征进行了分析.通过研究发现,所有的氢键复合物进行基组重叠误差(BSSE)校正后的相互作用能为-17.35～-43.27kJ/mol,相互作用能主要由氢键所贡献.振动分析显示,氢键的形成使相对应键的对称伸缩振动频率减小,说明这些复合物中形成的氢键都是正常的红移型氢键,与实验结果相一致.     

在遗传字母序列中新添两个字母

在此以前遗传字母序列中仅有四个字母(或碱基),即腺嘌呤(A),鸟嘌呤(G)、胸腺嘧啶(u或DNA的T)和胞嘧啶(C)。这些碱基通过氨基和羰基间的氢键使双链螺旋型RNA中的两条互补链结合在一起。其中,A与u形成两个氢键,G与C形成三个氢键,从而组成两个碱基对。生物世界就是靠这两个“碱基对”来运载遗传信息。最近,瑞士生物化学家Steven A.Benner证实其它碱基对亦可能运载遗传信息。例如,将鸟嘌呤或胞嘧啶中的羰基和氨基互相异位,可得到异嘌呤或异胞嘧啶。含这些非标准碱基的核苷酸能通过三个氢键作用形成所谓的Watson-Crick碱基对。     

O6-鸟嘌呤和O4-胸腺嘧啶甲基化与DNA碱基异常氢键作用的理论研究

用密度泛函B3LYP方法在6-311＋G**基组水平上对顺(cis-)、反式(anti-)O⁶-甲基鸟嘌呤(O⁶-MeG)和O⁴-甲基胸腺嘧啶(O⁴-MeT)与DNA碱基(腺嘌呤A、鸟嘌呤G)的非Watson-Crick氢键二聚体进行了优化. 在MP2/cc-pVXZ (X＝D,T)//B3LYP/6-311＋G**水平上, 采用完全基组外推方法校正了氢键二聚体的相互作用能, 并用完全均衡校正法(CP)校正了基组重叠误差(BSSE). 此外, 在B3LYP/6-311＋G**水平上计算了各氢键碱基对的全电子波函数, 并用分子中的原子理论(AIM)和电子密度拓扑方法分析了碱基间的弱相互作用. 计算结果显示, 甲基化使碱基对间的氢键作用模式发生了明显的扭转和不同程度的位移, 碱基间的电子密度分布和氢键作用能明显减小, 甲基化对O⁶-MeG和O⁴-MeT与DNA碱基间的氢键作用是去稳定化的, 这种影响主要来自于大体积的甲基的空间效应和给电子效应, 且对顺式的影响明显大于反式. 计算结果与文献给出的实验结论基本一致.     

人体端粒中(3+1)混合结构G-四链体稳定性的分子动力学模拟

利用分子动力学模拟方法, 考察了人体端粒中(3+1)混合结构G-四链体的结构及稳定性问题. 讨论了配位K+离子、药物分子(端粒抑素)和溶剂水分子对G-四链体的Hoogsteen氢键结构、π-π堆积作用的影响. 研究表明, K+离子与鸟嘌呤碱基上O6原子的配位作用减弱了对角鸟嘌呤间O6-O6的静电排斥作用, 使得相邻的四个鸟嘌呤能够以Hoogsteen氢键结合的方式形成具有近平面结构的稳定G-四平面. 另一方面, G-四平面间、G-四平面与药物分子间的π-π堆积作用降低了G-四链体复合物的总能, 有利于其稳定存在. 此外, 溶剂水分子主要分布在G-四链体的TTA环、骨架和糖环的周围, 使其位移涨落增大; 然而, 在3 ns动力学模拟中, 由于水分子没有进入到G-四链体的空腔中, 溶剂水对G-四平面的结构影响不明显.     

氨基酸侧链与氧化鸟嘌呤碱基对体系的氢键作用

应用量子化学方法,分别在气相和水溶液中对氨基酸侧链与氧化鸟嘌呤碱基对(8-oxo-G∶C)形成的三体复合物的氢键键能、几何结构、电荷分布及二阶稳定化能进行了研究.结果表明,水溶液的存在削弱了复合物中的氢键强度,电荷分布变化明显,水溶液中形成氢键位点的电荷变化量约为气相中的10倍,而几何结构变化不明显、对于酶与DNA之间的相互作用的研究需在水溶液中进行.水溶液对带电三体复合物中8-oxo-G∶C与氨基酸侧链间的氢键有较大影响,键能平均减小了69.23 k J/mol,不带电复合物仅减小了3.60k J/mol.水溶液中三体复合物中8-oxo-G∶C间的氢键受侧链的影响不大,且与侧链带电与否无关,带电复合物和不带电复合物的氢键强度分别减小了24.57和30.05 k J/mol,且二阶稳定化能越大,其对应的氢键键长越短.     

The solvation, partitioning, hydrogen bonding, and dimerization of nucleotide bases: a multifaceted challenge for quantum chemistry

We present M06-2X density functional calculations of the chloroform/water partition coefficients of cytosine, thymine, uracil, adenine, and guanine and calculations of the free energies of association of selected unsubstituted and alkylated nucleotide base pairs in chloroform and water. Both hydrogen bonding and π-π stacking interactions are considered. Solvation effects are treated using the continuum solvent models SM8, SM8AD, and SMD, including geometry optimization in solution. Comparison of theoretical results with available experimental data indicates that all three of these solvation models predict the chloroform-water partition coefficients for the studied nucleobases qualitatively well, with mean unsigned errors in the range of 0.4-1.3 log units. All three models correctly predict the preference for hydrogen bonding over stacking for nucleobase pairs solvated in chloroform, and SM8, SM8AD, and SMD show similar accuracy in predicting the corresponding free energies of association. The agreement between theory and experiment for the association free energies of the dimers in water is more difficult to assess, as the relevant experimental data are indirect. Theory predicts that the stacking interaction of nucleobases in water is more favorable than hydrogen bonding for only two out of three tested hetero-dimers.     

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.     

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.     

MP2 study on the hydrogen-bonding interaction between 5-hydroxymethyl-uracil and DNA bases: A,C, G,T

The 5-hydroxymethyl-uracil (HmU) is a product of oxidative attack on the methyl group of thymine in DNA. In this work, we present the hydrogen bonding complexes formation involving HmU bound to the four bases in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). Full geometry optimizations have been performed for the studied complexes by MP2 method. The interaction energies were corrected for the basis-set superposition error (BSSE), using the full Boys-Bernardi counterpoise correction scheme. Hydrogen bonding patterns of these base pairs were characterized using NBO analysis and AIM analysis. According to the calculated binding energies and structural parameters, the stability of the base pairs decrease in the following order: HmU:A > HmU:G > HmU:C > HmU:T.     

MP2 study on the hydrogen bonding interaction between 5-hydroxy-5-methylhydantoin and DNA bases: A,C, G,T

The 5-hydroxy-5-methylhydantoin (5-OH-5-Me-dHyd) is a nucleobase lesion induced by the action of ionizing radiation on thymine residue in DNA. In this study, we present the hydrogen bonding base pairs involving 5-OH-5-Me-dHyd bound to the four bases in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). Full geometry optimizations have been performed for the studied complexes by MP2 method. The interaction energies were corrected for the basis-set superposition error (BSSE), using the full Boys–Bernardi counterpoise correction scheme. Hydrogen bonding patterns of these base pairs were characterized using NBO analysis and AIM analysis. According to the calculated binding energies and structural parameters, the stability of the base pairs decrease in the following order: 5-OH-5-Me-dHyd:G>5-OH-5-Me-dHyd:A>5-OH-5-Me -dHyd:C~5-OH-5-Me-dHyd:T.     

Na+, Mg2+, and Zn2+ binding to all tautomers of adenine, cytosine, and thymine and the eight most stable keto/enol tautomers of guanine: a correlated ab initio quantum chemical study

Interactions of adenine, cytosine, guanine, and thymine with Na(+), Mg(2+), and Zn(2+) cations were studied using an approximate resolution of identity correlated second-order MP2 (RI-MP2) method with the TZVPP ([5s3p2d1f/3s2p1d]) basis set. All existing tautomers of adenine, cytosine, and thymine and the eight most stable keto/enol tautomers of guanine were considered. Cations bind mostly in a bidentate manner, and stabilization energies of these complexes are larger than those in the case when cations bind in a unidentate manner. The cation...Y (Y equal to N or O) distances for divalent metals are shorter than those for Na(+) and for Zn(2+) are mostly shorter than the Mg(2+)...Y distance. The intermolecular distances between the cation and the base for complexes containing adenine and cytosine are systematically shorter than those for complexes containing guanine and thymine. Only for cytosine the canonical keto/amino tautomer structure with ions represents the global minimum. For guanine, the metalated canonical form is again the most stable, but its stabilization energy is within less than 5% of the stabilization energies of the two other rare tautomers, which indicates that the canonical form and these two rare tautomers could coexist. The canonical structures of adenine and thymine in the presence of ions are considerably less stable (by more than 10%) than the complexes of the rare tautomers. It can be concluded that the interaction of Na(+), Mg(2+), and Zn(2+) cations with cytosine in the gas phase will not induce the change of the canonical form to the rare tautomeric form. In the case of isolated guanine, the equilibrium of the canonical form with rare tautomers can be found. For isolated adenine and thymine the presence of rare tautomers is highly probable.     

Insights into DNA binding of ruthenium arene complexes: role of hydrogen bonding and pi stacking

Density functional theory (DFT) methods are used to investigate the binding of ruthenium arene complexes, proposed as promising anticancer drugs, to isolated nucleobases. This shows a clear preference for binding at guanine over any other base and an approximately 100 kJ mol (-1) difference in binding between guanine and adenine in the gas phase, while binding to cytosine and inosine are intermediate in energy between these extremes. Solvation reduces binding energies and the discrimination between bases but maintains the overall pattern of binding. DFT and ab initio data on arene-base interactions in the absence of ruthenium show that stacking and hydrogen-bonding interactions play a significant role but cannot account for all of the energy difference between bases observed. Atoms-in-molecules analysis allows further decomposition of binding energies into contributions from covalent-binding, hydrogen-bonding, and pi-stacking interactions. Larger arenes undergo stabilizing stacking interactions, whereas N-H...X hydrogen bonding is independent of arene. Pairing of guanine to cytosine is affected by ruthenium complexation, with individual hydrogen-bonding energies being altered but the overall pairing energy remaining almost constant.     

DFT and MP2 investigations on the hydrogen bonding interaction between 5,6-dihydrothymine and dna bases: A, C, G, T

5,6-Dihydrothymine (DHT) is a nucleobase lesion induced by the action of ionizing radiation on thymine residue in DNA. In this work, we present the hydrogen bonding base pairs involving 5,6-dihydrothymine bound to four bases in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). Full geometry optimizations are performed for the studied complexes by the B3LYP method. Interaction energies are corrected for the basis set superposition error, using the full Boys-Bernardi counterpoise correction scheme. Hydrogen bonding patterns of these base pairs are characterized using NBO and AIM analysis. According to the calculated binding energies and structural parameters, the stability of the base pairs decrease in the following order: DHT:G ～ DHT:A > DHT:C > DHT:T.     

Molecular orbital theory of the hydrogen bond : XXXII. The effect of H and Li association on the A---T and G---C pairs

Ab initio molecular orbital calculations have been performed to determine the structures and stabilization energies of the A---T and G---C base pairs and their complexes with H⁺ and Li⁺, H⁺ and Li⁺ association stabilizes the A---T pair except for Li⁺ association at O₄ in thymine. Protonation of thymine stabilizes the A---T pair to a greater extent than protonation of adenine. The association of H⁺ and Li⁺ with guanine stabilizes the G---C pair, but protonation of cytosine destabilizes G---C. Changes in the structures of the hydrogen bonds in the A---T and G---C pairs reflect changes in hydrogen bond strengths.