金属卟啉对杂环及DNA分子识别研究进展

介绍了近几年国内外关于组装金属卟啉对杂环分子、DNA碱基以及RNA的分子识别的研究进展, 并简述了本课题组对金属卟啉与杂环及药物分子复合物的理论研究工作. 金属卟啉广泛存在于自然界和生物体中, 此识别过程对研究和模拟生命体中各种细胞之间的相互作用具有重要意义. 组装后的金属卟啉可通过轴向配位、氢键及π-π堆积作用等识别杂环分子. 金属卟啉对DNA的识别主要有四种作用方式, 而金属卟啉对DNA以及RNA分子的识别主要靠疏水作用力、静电力以及自堆叠作用. 卟啉阳离子与DNA的结合位点受主体侧链取代基的空间结构影响. 金属卟啉对药物分子的识别靠配位键和氢键进行, 以配位键结合的复合物通常具有更高的结合能.     

带电组氨酸侧链与DNA碱基间非键作用强度的理论研究

采用MP2方法和6-31+G(d,p)基组优化得到了带有一个正电荷的组氨酸侧链与4个DNA碱基间形成的18个氢键复合物的气相稳定结构, 从文献中获取了组氨酸侧链与DNA碱基间形成的12个堆积和T型复合物的气相稳定结构, 使用包含基组重叠误差(BSSE)校正的MP2方法和aug-cc-pVTZ基组及密度泛函理论M06-2X-D3方法和aug-cc-pVDZ基组计算了这些复合物的结合能. 研究结果表明, 包含BSSE校正的M06-2X-D3方法和aug-cc-pVDZ基组能够给出较准确的结合能; 气相条件下, 组氨酸侧链与同种DNA碱基间的离子氢键作用明显强于堆积作用和T型作用, 组氨酸侧链最易通过离子氢键与胞嘧啶C和鸟嘌呤G作用形成氢键复合物, 组氨酸与胞嘧啶C和鸟嘌呤G间的T型作用强于与腺嘌呤A和胸腺嘧啶T间的离子氢键作用; 水相条件下, 组氨酸侧链与同种DNA碱基间的离子氢键作用仍明显强于堆积作用和T型作用, 组氨酸侧链更易与胞嘧啶C和鸟嘌呤G相互作用形成氢键复合物, 但是最强的组氨酸侧链与胞嘧啶C间的T型作用明显弱于与腺嘌呤A和胸腺嘧啶T间的离子氢键作用, 说明水相条件下组氨酸侧链与DNA碱基间主要通过离子氢键作用形成氢键复合物.     

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.     

核酸四碱基体的量子化学计算

应用量子化学半经验ＣＮＤＯＭＯ方法，对核酸碱基间可能形成的四碱基体进行计算．结果显示，除了实验中已确认存在的两种四碱基体Ｇ４和Ｇ·Ｃ·Ｇ·Ｃ外，还有６种以Ｗａｔｓｏｎ－Ｃｒｉｃｋ碱基对形成的四碱基体也能稳定存在．通过对Ｇ４碱基体分子间、离子－分子间相互作用的考查，进一步证实了氢键、四碱基体间的堆积作用、金属离子与四碱基体的相互作用等，对于四螺旋核酸结构的形成是重要的．     

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.     

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.     

量子化学研究水对Adenine-Thymine碱基对构型的影响

利用Hartree-Fock方法, 选取6-31G*基组对Adenine-Thymine-Water氢键复合物可能存在的构型进行了优化, 然后用DFT PBE方法, 选取6-311＋＋G(3d, 3p)基组对复合物的结合能进行计算, 结果表明水与DNA中配对碱基的相互作用, 不会显著影响碱基对的稳定性, 水的存在使得碱基对的扭转构型更接近真实DNA中碱基对的螺旋状结构.     

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.     

Fapy-G对碱基氢键复合物影响的理论研究

应用量子化学方法对2,6-二氨基-4-羟基-5-甲酰胺嘧啶(Fapy-G)与正常碱基作用形成的20种氧化碱基对的多种性质进行了理论分析,碱基G的C8位被氧化后N7和N9位分别增加一个H原子,使其由氢键受体变成氢键供体,N7,N9及O6原子所带的电荷变负,同时O6作为氢键受体的能力增强.与碱基单体相比,碱基对中形成氢键的受体原子所带的电荷平均减小0.05 e;供体H原子所带的电荷平均增大0.02 e.Fapy-G分子中六元环上受体N原子参与形成氢键时,环的呼吸振动模式和N与对位C的振动模式的振动频率蓝移;与氢键相关的振动频率红移.所有氧化碱基对中,NH…N比NH…O氢键作用更强,且在NH…N氢键中,在六元环上的供体N原子形成的氢键比在氨基或开环上的供体N原子形成的氢键强.Fapy-G与碱基A作用结合能区域顺序为1>2>4>3,与碱基T(R)作用区域顺序为3=4>1>2;水溶液使Fapy-G与碱基C作用的结合能减弱程度最大,结合能达到41.84~58.58 k J/mol,且使碱基对结合能力次序发生改变.     

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.     

Stabilization of an all-metal antiaromatic molecule (Al4Li4) using BH and C as caps

It has been reported by Pati et al. ( J. Am. Chem. Soc. 2005, 127, 3496) that coordination with a transition metal can stabilize the "antiaromatic", all-metal compound Al4Li4. Here, we report that it can also be stabilized by capping with a main group element like C and its isoelectronic species BH. Our calculations of binding energy, nuclear independent chemical shift, energy decomposition analysis, and molecular orbital analysis support the capping-induced stability, reduction of bond length alternation, and increase of aromaticity of these BH/C-capped Al4Li4 systems. The interaction between px and py orbitals of BH/C and the HOMO and LUMO of Al4Li4 is responsible for the stabilization. Our calculations suggest that capping can introduce fluxionality at room temperature.     

Amineborane-based chemical hydrogen storage: enhanced ammonia borane dehydrogenation in ionic liquids

Ionic liquids are shown to provide advantageous media for amineborane-based chemical hydrogen storage systems. Both the extent and rate of hydrogen release from ammonia borane dehydrogenation are significantly increased at 85, 90, and 95 degrees C when the reactions are carried out in 1-butyl-3-methylimidazolium chloride compared to analogous solid-state reactions. NMR studies in conjunction with DFT/GIAO chemical shift calculations indicate that both polyaminoborane and the diammoniate of diborane, [(NH3)2BH2+]BH4-, are initial products in the reactions.     

Thermodynamic properties of molecular borane amines and the [BH4-][NH4+] salt for chemical hydrogen storage systems from ab initio electronic structure theory

The heats of formation for the borane amines BH3NH3, BH2NH2, and HBNH, tetrahedral BH4-, and the BN molecule have been calculated by using ab initio molecular orbital theory. Coupled cluster calculations with single and double excitations and perturbative triples (CCSD(T)) were employed for the total valence electronic energies. Correlation consistent basis sets were used, up through the augmented quadruple-zeta, to extrapolate to the complete basis set limit. Core/valence, scalar relativistic, and spin-orbit corrections were included in an additive fashion to predict the atomization energies. Geometries were calculated at the CCSD(T) level up through at least aug-cc-pVTZ and frequencies were calculated at the CCSD(T)/aug-cc-pVDZ level. The heats of formation (in kcal/mol) at 0 K in the gas phase are Delta Hf(BH3NH3) = -9.1, Delta Hf(BH2NH2) = -15.9, Delta Hf(BHNH) = 13.6, Delta Hf(BN) = 146.4, and Delta Hf(BH4-) = -11.6. The reported experimental value for Delta Hf(BN) is clearly in error. The heat of formation of the salt [BH4-][NH4+](s) has been estimated by using an empirical expression for the lattice energy and the calculated heats of formation of the two component ions. The calculations show that both BH3NH3(g) and [BH4-][NH4+](s) can serve as good hydrogen storage systems which release H2 in a slightly exothermic process. The hydride affinity of BH3 is calculated to be 72.2 kcal/mol, in excellent agreement with the experimental value at 298 K of 74.2 +/- 2.8 kcal/mol.     

Calculation of the correlation energy of molecules by many-body rayleigh-schrödinger perturbation theory up to third order

The correlation energy of the H₂O, BH, HF and Ne systems is calculated by many-body Rayleigh-Schrödinger perturbation theory up to third order, and compared with CI calculations in exactly the same basis sets.     

Role of NH3 in the dehydrogenation of calcium amidoborane ammoniate and magnesium amidoborane ammoniate: a first-principles study

First-principles calculations show that [NH(3)] molecules play crucial roles as both activator for the break-up of B-H bond and supplier of protic H for the establishment of dihydrogen bonding, which could facilitate the dehydrogenation of Ca(NH(2)BH(3))(2)·2NH(3) or Mg(NH(2)BH(3))(2)·NH(3) occurring at lower temperatures compared to those of Ca(NH(2)BH(3))(2) and Mg(NH(2)BH(3))(2). Moreover, the calculations of Helmholtz Free energy and [NH(3)] molecule removal energy evidence that coordination between [NH(3)] and Mg cation is stronger than that between [NH(3)] and Ca cation; therefore, Mg(NH(2)BH(3))(2)·NH(3) will undergo directly dehydrogenation rather than deammoniation at lower temperatures.     

LICHEM: A QM/MM program for simulations with multipolar and polarizable force fields

We introduce an initial implementation of the LICHEM software package. LICHEM can interface with Gaussian, PSI4, NWChem, TINKER, and TINKER–HP to enable QM/MM calculations using multipolar/polarizable force fields. LICHEM extracts forces and energies from unmodified QM and MM software packages to perform geometry optimizations, single‐point energy calculations, or Monte Carlo simulations. When the QM and MM regions are connected by covalent bonds, the pseudo‐bond approach is employed to smoothly transition between the QM region and the polarizable force field. A series of water clusters and small peptides have been employed to test our initial implementation. The results obtained from these test systems show the capabilities of the new software and highlight the importance of including explicit polarization. © 2016 Wiley Periodicals, Inc.     

Reductive openings of acetals: explanation of regioselectivity in borane reductions by mechanistic studies

The mechanisms of regioselective reductive openings of acetals were investigated in several model systems by a combination of Hammett plots, kinetic experiments, density functional calculations, and (11)B NMR. The regioselectivity of borane reductions of cyclic acetals can be controlled by the choice of borane. Lewis acid activation of BH3 x NMe3 increases the reaction rate and renders the borane the most electrophilic species, which associates to the more electron-rich oxygen of the acetal. In contrary, without activation, the regioselectivity is instead directed by the Lewis acid, as exemplified by the reaction with BH3 x THF.     

Electronic structure of M(BH4)4, M = Zr, Hf, and U, by variable photon-energy photoelectron spectroscopy and density functional calculations

Photoelectron (PE) spectra have been obtained for the M(BH(4))(4) (M = Zr, Hf and U) molecules in the 20-60 eV photon-energy range, and for M = U, also in the 90-120 eV region. Derived branching ratios (BR) and relative partial-photoionization cross sections (RPPICS) of the valence bands are used to confirm band assignment and demonstrate d-orbital covalency for all three compounds and f-orbital covalency for U(BH(4))(4). Core ionizations are identified and used to confirm resonance features in the RPPICS. The absorption spectrum of Zr(BH(4))(4) between 20 and 60 eV shows 4p absorption at 35.5 eV, coincident with the 4p-4d resonance in the RPPICS of the 1e and 2t(2) ionization bands of Zr(BH(4))(4). Less intense absorption bands at 32.5 and 33.8 eV correspond with shape resonance features in the 1a(1) and 1t(2) PE bands. The RPPICS of the f band of U(BH(4))(4) shows two strong resonant features between 95 and 120 eV. Direct photoemission of the 5f electrons from U(BH(4))(4) results only in the observation of the (2)F(5/2) ion state of [U(BH(4))(4)](+), but in the 5d-5f resonant region, a weak band corresponding to the (2)F(7/2) ion state is also observed. The splitting of the 1t(2) band of U(BH(4))(4) is attributed to a small contribution of U 6p semi-core electrons to this MO. Density functional calculations give a good estimate of the pattern of ionization energies, although the calculated absolute values are lower than the experimental values, the first IE by 0.5 eV for Zr(BH(4))(4) and Hf(BH(4))(4) and 1.0 eV for U(BH(4))(4). The MO compositions are in very good agreement with the deductions made from the BR and RPPICS analyses.     

A semiempirical approach to ligand‐binding affinities: Dependence on the Hamiltonian and corrections

We present a combination of semiempirical quantum‐mechanical (SQM) calculations in the conductor‐like screening model with the MM/GBSA (molecular‐mechanics with generalized Born and surface‐area solvation) method for ligand‐binding affinity calculations. We test three SQM Hamiltonians, AM1, RM1, and PM6, as well as hydrogen‐bond corrections and two different dispersion corrections. As test cases, we use the binding of seven biotin analogues to avidin, nine inhibitors to factor Xa, and nine phenol‐derivatives to ferritin. The results vary somewhat for the three test cases, but a dispersion correction is mandatory to reproduce experimental estimates. On average, AM1 with the DH2 hydrogen‐bond and dispersion corrections gives the best results, which are similar to those of standard MM/GBSA calculations for the same systems. The total time consumption is only 1.3–1.6 times larger than for MM/GBSA. © 2012 Wiley Periodicals, Inc.