量子化学在生物分子领域的研究进展

量子化学的方法对生物分子研究的发展提供了全新的思路和方法。本文介绍了量子化学的基本计算方法,并综述了近两年来量子化学方法在生物分子领域的研究进展。     

应用量子化学方法研究生育酚结构与抗氧化活性的关系

采用分子力学和量子化学从头计算方法,研究分析不同分子结构的生育酚和一些酚类化合物所具抗氧化作用的构效关系。生育酚的抗氧化活性与易释放活泼氢有关,活性大小与Ｏ－Ｈ间电子集居数、前线轨道能级及反应终态能量下降值有关,各种生育酚模型分子的羟基Ｏ－Ｈ电子集居数排列顺序α＜γ≤β＜δ,生育酚自由基转变为醌结构,终态能量下降值顺序为α＞γ≥β＞δ,与文献报道抗氧化活性的结论相一致。应用量子化学指数可以帮助分析具有不同结构的酚类化合物的抗氧化活性     

西文新书介绍

《量子化学展望:第六届国际量子化学会议大会演讲集》(Perspectives in quantumchemistry:plenary lectures presented at the sixth international congress onquantum chemistry)由Joshua Jortner和Bernard Pullman编著,1989年Kluwer学术出版社出版,164页。该书可供量子、分子、化学、生物学家参考使用。第六届国际量子化学会议于1988年8月22—25日在以色列耶鲁撒冷希伯来大学召开。该会议由量子分子科学国际学院主办。以前会议曾在法国、日本、美国、瑞典和加拿大召开。该次会议在现代理论化学的重要领域里作出贡献。     

部分镇痛药的分子模拟及其量化计算

采用分子力学和量子化学方法对某些作用于脑啡肽酶的硫乙内酰脲衍生物（YL－2、YL－12、YL－3和YL－11）的化学结构进行了分析模拟和量化计算。优化了各化合物的空间结构,得到了优势构象和优势构象的能量,研究了分子的电荷分布,前线轨道能量等。供助于理论计算可解释脑啡肽酶抑制剂的构效关系,对其活性差异给予较好的分析,可望为合成具有更高药效的无成瘾性镇痛药提供理论指导。     

正常和反常PRION分子PrP~C和PrP~(Sc)的空间结构模建和电子结构计算

朊蛋白（ＰＲＩＯＮ） 是一种不同于细菌,真菌,病毒的新的病原体。１９９６ 年英国“疯牛病”引起了对ＰＲＩＯＮ 研究的高潮。ＰＲＩＯＮ 分子生物学研究的关键是解释ＰＲＩＯＮ 蛋白构象转换的生物学本质。本文从构象模建,量子化学整体从头算的水平上对两个构象的电子结构进行了计算比较,从中发现了ＰＲＩＯＮ 蛋白分子电子结构上区别于其他分子的特异性, 并对计算所得的活性部位进行了讨论。     

肼基单胺氧化酶抑制剂活性与电子结构构效关系的计算分析

采用量子化学方法,在DFT/B3LYP/6-31G*基组水平上对肼基单胺氧化酶抑制剂进行了几何构型优化和电子结构计算.根据计算结果,分析了肼基单胺氧化酶抑制剂的抑制活性与电子结构的构效关系,结果表明,肼基单胺氧化酶抑制剂衍生物的活性与最低空轨道的能量E_LUMO与最高占据轨道的能量E_HOMO的差值、分子偶极矩和苯环上5位碳原子电荷密度有显著相关性.     

正常和反常PRION分子PrP~C和PrP~(Sc)的空间结构模建和电子结构计算

朊蛋白（ＰＲＩＯＮ）是一种不同于细菌,真菌,病毒的新的病原体。１９９６年英国“疯牛病”引起了对ＰＲＩＯＮ研究的高潮。ＰＲＩＯＮ分子生物学的关键是解释ＰＲＩＯＮ蛋白构象转换的生物不本质。本文从构象模建,量子化学整体从头算的水平上对两个构象的电子结构进行了计算比较,从中发现了ＰＲＩＯＮ蛋白分子电子结构上区别于其他分子的特异性,并对计算所得的活性部位进行了讨论。     

蛋白质分子络合物的电子结构与氧化还原反应

本文用量子化学方法研究蛋白质分子格合物的电子能谱及电子转移和氧化还原反应的关系。本文的结果表明:当蛋白质分子和辅酶或其它有机分子形成电荷迁移络合物时,在蛋白质分子导带下面将出现一系列定域化的电子-空穴束缚态能级。络合物受激发时,首先由基态跃迁到束缚态最低能级,出现电荷迁移吸收光谱。再激发时,才能由束缚态最低能级跃迁到其它束缚态能级或导带,从而出现非定域化的电子和产生电子顺磁共振信号。极性介质的影响和化学反应有助于电子转移。而络合物中的电子转移又会导致电子施主分子被氧化,电子受主分子被还原。通过对辅酶等分子的电离能和电子亲合势的计算,说明辅酶和蛋白质分子可能以电荷迁移络合物的形式存在。一些半定量的计算和定性的结论能初步解释氧化还原酶在光激发和酶促反应中所产生的电荷迁移吸收光谱及电子顺磁其振信号的实验事实。     

α（1→4）连接的半乳糖醛酸构象的量子化学研究

本文采用量子化学ＳＣＦ－ＭＯ－ＬＣＡＯ半经验方法,对二聚半乳糖醛酸的构象从理论上进行了研究。在势能面上存在多个构象区域稳定点,最稳定的构象形式在Φ＝６０．０°,ψ＝－１２０．０°位置。从量子化学的前线分子轨道、电荷布后以及双中心作用能分析探讨了稳定构象与水解易于发生的可能构象间的联系。为生物化学研究提供了必要的信息。     

棉酚对鱼精DNA作用的量子生物学研究

紫外吸收光谱显示棉酚与DNA相互作用没有共价键形成.也不生成电荷迁移络台物.量子化学计算棉酚与胸腺嘧啶分子中的净电荷分布,发现沿两者结构式粗线上各原子的电荷恰好符号相反(图2).这表示棉酚很可能以共轭平面平行地插入到DNA分子双螺旋结构的碱基片层之间,与其中的胸腺嘧啶碱基以弱相互作用的极性键形成复合物.这种结合是可逆的,不影响DNA的一级结构.     

Calculation of spectral shifts of the mutants of bacteriorhodopsin by QM/MM methods

In the present work spectral shifts of adsorption maxima for the number of mutants of bacteriorhodopsin have been calculated using QM/MM hybrid methodology. Along with this calculation an analysis of possible mechanisms of spectral modulation has been performed. Also we have carried out a comparative analysis of modern quantum chemical methods in respect of the level of optical spectra predictability they allow. We have shown that modern hybrid quantum chemical methods reach an acceptable level of preciseness when applied in the calculation of spectral shifts even if the absolute values of adsorption maxima predicted by these methods are underestimated. The number of rules has been found linking the value of spectral shift with the structural rearrangement in the apoprotein. The methods we were using as well as those rules we have found out both may be useful for development of nanoelectronical devices based on mutant species of bacteriorhodopsin (memory elements, optical triggers etc.).     

Calculation of spectral shifts of the mutants of bacteriorhodopsin by QM/MM methods

Spectral shifts of adsorption maxima for a number of mutants of bacteriorhodopsin have been calculated using QM/MM hybrid methodology. Along with this calculation, an analysis of possible mechanisms of spectral modulation has been performed. Also we have carried out a comparative analysis of modern quantum chemical methods in respect of the level of optical spectra predictability they allow. We have shown that modern hybrid quantum chemical methods reach an acceptable level of preciseness when applied in the calculation of spectral shifts even if the absolute values of adsorption maxima predicted by these methods are underestimated. A number of rules has been found linking the value of spectral shift with the structural rearrangement in the apoprotein. The methods we were using as well as those rules we have found out both may be useful for development of nanoelectronical devices based on mutant species of bacteriorhodopsin (memory elements, optical triggers etc.).     

Gas phase infrared spectra via the phase integration quasi-classical method

We apply the recently developed phase integration method (PIM) (Monteferrante et al. Mol Phys. 2011;109:3015–3027) to the calculation of infrared spectra of gas phase molecules. The PIM combines a generalised Monte Carlo sampling of the exact thermal density of the system with classical molecular dynamics to obtain approximate time quantum correlation functions. To describe the molecules, we adopt very simple analytical potentials that have, however, proved interesting, and surprisingly challenging, benchmarks for approximate quantum dynamical schemes. We show that, in contrast with two other commonly applied methods, our spectra do not exhibit spurious features or unphysical shifts depending on the temperature. Identifying the positions of the peaks requires only a few tens of trajectories, while an accurate evaluation of the relative intensities of the peaks is computationally more demanding.     

Computer-simulation-based selection of optimal monomer for imprinting of tri-O-acetyl adenosine in a polymer matrix: calculations for benzene solution

Molecular imprinting is a promising way to create polymer materials that can be used as artificial receptors, and have anticipated use in synthetic imitation of natural antibodies. In case of successful imprinting, the selectivity and affinity of the imprint for the substrate molecules are comparable with those of natural counterparts. Various calculation methods can be used to estimate the effects of a large range of imprinting parameters under different conditions, and to find better ways to improve polymer characteristics. However, one difficulty is that properties such as hydrogen bonding can be modeled only by quantum methods that demand a lot of computational resources. Combined quantum mechanics/molecular mechanics (QM/MM) methods allow the use of MM and QM for different parts of the modeled system. In present study this method was realized in the NWChem package to compare estimations of the stability of tri-O-acetyl adenosine–monomer pre-polymerization complexes in benzene solution with previous results under vacuum.     

Accurate ab initio prediction of NMR chemical shifts of nucleic acids and nucleic acids/protein complexes

NMR chemical shift predictions based on empirical methods are nowadays indispensable tools during resonance assignment and 3D structure calculation of proteins. However, owing to the very limited statistical data basis, such methods are still in their infancy in the field of nucleic acids, especially when non-canonical structures and nucleic acid complexes are considered. Here, we present an ab initio approach for predicting proton chemical shifts of arbitrary nucleic acid structures based on state-of-the-art fragment-based quantum chemical calculations. We tested our prediction method on a diverse set of nucleic acid structures including double-stranded DNA, hairpins, DNA/protein complexes and chemically-modified DNA. Overall, our quantum chemical calculations yield highly/very accurate predictions with mean absolute deviations of 0.3–0.6 ppm and correlation coefficients (r²) usually above 0.9. This will allow for identifying misassignments and validating 3D structures. Furthermore, our calculations reveal that chemical shifts of protons involved in hydrogen bonding are predicted significantly less accurately. This is in part caused by insufficient inclusion of solvation effects. However, it also points toward shortcomings of current force fields used for structure determination of nucleic acids. Our quantum chemical calculations could therefore provide input for force field optimization.     

Three applications of path integrals: equilibrium and kinetic isotope effects, and the temperature dependence of the rate constant of the [1,5] sigmatropic hydrogen shift in (Z)-1,3-pentadiene

Recent experiments have confirmed the importance of nuclear quantum effects even in large biomolecules at physiological temperature. Here we describe how the path integral formalism can be used to describe rigorously the nuclear quantum effects on equilibrium and kinetic properties of molecules. Specifically, we explain how path integrals can be employed to evaluate the equilibrium (EIE) and kinetic (KIE) isotope effects, and the temperature dependence of the rate constant. The methodology is applied to the [1,5] sigmatropic hydrogen shift in pentadiene. Both the KIE and the temperature dependence of the rate constant confirm the importance of tunneling and other nuclear quantum effects as well as of the anharmonicity of the potential energy surface. Moreover, previous results on the KIE were improved by using a combination of a high level electronic structure calculation within the harmonic approximation with a path integral anharmonicity correction using a lower level method.     

分子模拟方法及其在分子生物学中的应用

常用的分子模拟方法有 :量子力学法、分子力学方法、蒙特卡洛法和分子动力学法。四种方法各有优势 ,共同成为分子模拟的组成部分。综述了分子模拟法在分子生物学中的应用 ,最后介绍了分子模拟的发展方向 ,并预测了其未来的发展趋势。常用的分子模拟方法有 :量子力学法、分子力学方法、蒙特卡洛法和分子动力学法。四种方法各有优势 ,共同成为分子模拟的组成部分。综述了分子模拟法在分子生物学中的应用 ,最后介绍了分子模拟的发展方向 ,并预测了其未来的发展趋势。     

Real-time nanoscopy by using blinking enhanced quantum dots

Superresolution optical microscopy (nanoscopy) is of current interest in many biological fields. Superresolution optical fluctuation imaging, which utilizes higher-order cumulant of fluorescence temporal fluctuations, is an excellent method for nanoscopy, as it requires neither complicated optics nor illuminations. However, it does need an impractical number of images for real-time observation. Here, we achieved real-time nanoscopy by modifying superresolution optical fluctuation imaging and enhancing the fluctuation of quantum dots. Our developed quantum dots have higher blinking than commercially available ones. The fluctuation of the blinking improved the resolution when using a variance calculation for each pixel instead of a cumulant calculation. This enabled us to obtain microscopic images with 90-nm and 80-ms spatial-temporal resolution by using a conventional fluorescence microscope without any optics or devices.