高压诱导小蛋白Chignolin变性的分子动力学研究

在温度为300 K,压强为200、1 000和2 000 MPa时,分别对小蛋白Chignolin进行了50 ns的分子动力学模拟,模拟中考虑了水的压缩性系数随压强的改变情况.结果表明,在高压下Chignolin的构象产生非常显著的变化,出现了完全去折叠.通过研究水和Chignolin之间氢键作用发现,两者之间的氢键数目变化趋势与蛋白质构象变化相一致.进一步研究还发现,压强的增大还会抑制Chignolin的去折叠;同时对高压诱导小蛋白变性的机理进行了分析.     

高压对朊蛋白构象和动力学的影响

蛋白质在溶液中是多种构象并存的一个热力学系统,不同的构象以一定的概率在不同的态之间互相转变。作为一个热力学体系,不同构象存在的概率受到热力学变量的影响,压强作为一个基本的热力学变量,其变化将影响到蛋白质的构象分布和动力学行为。压强的增大通常会减小蛋白质的体积,从而可以通过增大压强开展对常压下难以观察的构象进行研究,这些构象对于揭示蛋白质的生物学功能具有重要意义。以朊蛋白为研究对象,通过分子动力学模拟方法研究高压诱导下蛋白质的构象变化。研究结果表明:水分子在高压下的排列趋向于有序,水分子的有序排列直接影响到与水分子有密切接触残基的动力学行为;高压下水分子能够渗入二级结构的疏水核心,破坏β片层的二级结构。揭示高压诱导下朊蛋白构象转化的分子机制,为蛋白质的高压变性研究提供理论依据。     

2013-26 科技要闻

揭示植物激素作用新机制华中师范大学杨光富教授研究组在深入分析GID1-GA(GA,赤霉素;GID1,GIBBERELLIN INSENSITIVE DWARF1)复合体晶体结构的基础上,通过对GID1蛋白的构象进行微秒级的分子动力学模拟,首次发现了赤霉素与受体GID1蛋白结合的新通道,并提出了"非变构学说"的赤霉素作用新机制,即赤霉素在通过新通道与GID1蛋白结合时并不介导其氮端结构域发生构象变化,而是通过稳定GID1与DELLA蛋白之间的氢键而介导DELLA蛋     

蛋白质结构与动力学的计算机模拟：从方法到应用

计算机模拟已发展为根据生物分子结构和动力学阐释生物功能的重要工具.同现有实验比较,计算机模拟不仅能提供结构的时空平均,而且可获得任意微观量的时空分布和演化轨迹.除结构之外,生物功能往往依赖于对动力学的控制.计算机模拟可用于重构构象跃迁路径,发现中间体和过渡态等.本文总结了作者实验室在这一领域的近期工作,特别是关于能量模型、酶催化模拟、构象空间采样等.     

GaN量子点弹性模量的分子动力学模拟

 应用一种分子动力学的方法,模拟预测了氮化镓（GaN）量子点在应变状态下的弹性模量和体积模量.通过在闪锌矿和纤维锌矿两类模型上施加不同形式的应变,得出了体应变和系统能量之间的关系.进一步利用分子动力学方法模拟出系统的能量,并计算出GaN材料在应变状态的弹性模量.在零应变状态下,预测结果同以往的理论值和实验值相吻合.     

分子动力学模拟三氯生对烯脂酰-ACP还原酶作用机制研究

本文利用分子动力学模拟分别研究了蛋白sa Fab I体系、sa Fab I-NADP+体系和sa Fab I-NADP+-TCL体系的稳定性、各氨基酸残基随模拟时间的波动情况以及活性位点处关键氨基酸残基构象的变化规律.研究表明,辅酶NADP+及抑制剂三氯生均可在不同程度上促使蛋白构象稳定.辅酶NADP+可以促使活性位点Loop区残基Y147-Y157残基构象变为规则的卷曲构象;抑制剂三氯生可以促使蛋白与底物结合位点Loop I区残基I94-E108和Loop II区残基R194-F204及活性位点Loop区残基Y147-Y157残基构象变为规则的卷曲构象,构象趋于稳定.上述研究发现对认识三氯生作为抗菌药物机制及相关药物设计具有重要指导意义.     

Pim-1蛋白激酶与3,5-二取代吡唑并吡啶衍生物的分子识别研究

具有丝/苏氨酸激酶活性的Pim-1蛋白激酶(Pim-1 protein kinase,PPK)的过度表达能导致肿瘤的发生,是一个有效的抗肿瘤药物作用靶点.对PPK与3,5-二取代吡唑并吡啶衍生物(3,5-Disubstituted pyrazolopyridine derivatives,DPD)的复合物进行了20 ns的分子动力学模拟,从能量角度分析了二者结合的主要驱动力以及I 185在识别过程中的重要作用,并对复合物体系在模拟过程中的构象变化进行了分析.结果表明,PPK的核心区的保守性是其发挥生理功能的重要机制,模拟结果对基于PPK抑制剂的药物设计具有一定参考作用.     

蛋白质在溶液中构象转换的分子动力学模拟

将蛋白质的稳定和失活、折叠和去折叠等现象概括为蛋白质分子在溶液中的构象变化问题。采用非品格模型和Langevin分子动力学方法研究了无限稀释溶液及不同尺度和不同表面亲／疏水性球形限制性空间内β模型蛋白的构象分布及其转换特性。模拟结果显示：尺寸适度的疏水性空间有利于蛋白质结构发生缩塌,而亲水性空间有利于缩塌态蛋白质结构的稳定,且表面亲／疏水性的影响作用随着空间半径的增大而减弱。计算结果与实验报道一致,为研究蛋白质分子在溶液中的折叠和稳定化提供了理论工具。     

有限元和分子动力学结合的纳米梁研究方法

给出了一种新的有限元与分子动力学相结合的纳米梁的模拟方法.其基本思想是在分子动力学初始化的基础上进行有限元分析,在有限元分析结果的基础上通过分子动力学松弛模拟,这样既保证了计算结果的精度又使计算速度得到大幅度提高,克服了传统分子动力学效率低的缺点.通过纳米梁性能的研究实例详述了结合过程.     

小蛋白天然结构与折叠速度关系的分子动力学模拟研究

用分子动力学模拟方法研究了小蛋白天然结构集合与其折叠速度的关系．根据蛋白质内存在接触的不同定义方式．利用分子动力学模拟方法得到了10个小蛋白的一系列构象集合,分析了其拓扑参数与折叠速度的关系,并与PDB单构象的情况进行了比较．用含主链重原子的方式定义接触,所计算的结果较好,天然结构集合所计算的拓扑参数与蛋白质折叠速度的关系可以更真实地反映实际情况．     

Mapping the conformational wave of acetylcholine receptor channel gating

Allosteric transitions allow fast regulation of protein function in living systems. Even though the end points of such conformational changes are known for many proteins, the characteristics of the paths connecting these states remain largely unexplored. Rate-equilibrium linear free-energy relationships (LFERs) provide information about such pathways by relating changes in the free energy of the transition state to those of the ground states upon systematic perturbation of the system. Here we present an LFER analysis of the gating reaction pathway of the muscle acetylcholine receptor. We studied the closed <==> open conformational change at the single-molecule level following perturbation by series of single-site mutations, agonists and membrane voltages. This method provided a snapshot of several regions of the receptor at the transition state in terms of their approximate positions along the reaction coordinate, on a scale from 0 (closed-like) to 1 (open-like). The resulting map reveals a spatial gradient of positional values, which suggests that the conformational change proceeds in a wave-like manner, with the low-to-high affinity change at the transmitter-binding sites preceding the complete opening of the pore.     

Effects of extracellular calmodulin on pollen germination and tube growth

The effects of calmoddin (CaM) antagonist W7-agarose, anti-CaM serum and exogenous purified CaM on pollen germination and tube growth ofForsythia suspensu were studied. The pollen germination and tube growth were inhibited or completely stopped by CaM antagonist W7-agarose. The addition of exogenous purified CaM stimulated pollen germination and tube growth, whereas the same amount of bovine serum albumin (BSA) had no effect. The inhibitory effects caused by W7-agarose and anti-CaM serum could be reversed completely by the addition of exogenous purified CaM. The tube growth of germinated pollen was also inhibited or completely stopped by W7-agarose. The results suggest that endogenous extracellular CaM initiates pollen germination and tube growth, whereas exogenous CaM enhances the above processes.     

番茄碱对棉铃虫毒性分析

本文主要研究了番茄碱对棉铃虫的毒性作用．实验结果表明：（1）用不同浓度的番茄碱（tomatine）浸泡的棉花叶饲喂棉铃虫时，随浓度的增加及时间的延长，对棉铃虫的杀伤力增强．结果显示：饲喂第三天时，1mmol／L的浓度引起48％死亡，2mmol／L时60％死亡，4mmol／L时76％死亡，其IC50为1．78mmol／L．（2）用紫外光谱分析测得虫体内钙调蛋白的含量，结果显示：tomatine对其体内钙调蛋白的影响较大，随tomatine浓度的增加，钙调蛋白的含量逐渐降低．（3）紫外光谱图谱显示：番茄碱与钙调蛋白形成了一种新的物质（其特征吸收峰在190nm-220nm）．说明tomatine对棉铃虫的杀伤作用与钙调蛋白有关，此项研究为进一步探讨tomatine的作用分子机制提供了科学参数．     

关于无闭点的概型的注记

构造了一类无闭点概型,其中既存在包含着无穷多个无闭点开子概型的无闭点概型,也存在开子概型皆有闭点的无闭点概型。     

利用分子动力学方法研究吸附原子在Re(0001)表面的自扩散行为

利用分子动力学与分析型嵌入原子模型,研究了吸附原子在Re(0001)表面的自扩散行为.本文计算的扩散系数符合Arrhenius关系.扩散激活能与前因子从Arrhenius关系得到.计算的扩散激活能与低温场离子显微镜实验结果吻合,而前因子与一般理论计算结果相符.     

Involvement of Ca<Superscript>2+</Superscript>/CaM in the signal transduction of acetylcholine regulating stomatal movement

It has been known that the neurotransmitter acetylcholine (ACh) also exists in plants and is able to regulate the movement of stomata.In another aspect,Ca^2 /CaM as the second messengers have a critical role of signal transduction in stomatal guard-cell,Here we showed that Ca^2 /CaM were also involved in the ACh regulated stomatal movement,In the medium containing Ca^2 ,the Ca^2 channel blockers (NIF and Ver)and CaM inhibitors (TFP and W7 ) could neutralize the ACh induced stomatal opening,however,they are ineffective in the medium containing K^ ,Those results indicated that Ca^2 /CaM were involved in the signal transduction pathway of ACh regulating stomatal movement.     

Docking and molecular dynamics studies on CYP2D6

Drug-metabolizing enzymes, also known as cytochrome P450s, are a superfamily of hemoglobin responsible for metabolizing more than 90% clinical drugs. Cytochrome P450 2D6 (CYP2D6) is a significant member of cytochrome P450s for the reason of metabolizing about 20% clinical drugs. In this paper, molecular docking and molecular dynamic simulations are used to investi- gate the active site of CYP2D6, roles of essential amino acids within the active site and time-dependent protein energy changes. The results suggest that amino acids Glu216, Asp301, Ser304 and Ala305 in the active site are likely to form hydrogen bonding interac-tions with substrates; the benzene ring of Phe120 and aromatic ring in the substrates form ∏-∏ interactions. In addition, molecular dynamics simulations prove that the catalytic conformation of CYP2D6 without ligands can be obtained by their own atomic fluctuations. The impact of ligands on protein system energy and large conformational shift is not very large. Cytochrome P450s is known for their genetic polymorphisms, which will result in severe adverse drug reactions. Ideally, we hope to use mo- lecular modeling to investigate the differences between the substrates of wild-type and mutants while they are bonded with drugs, and predict the drug metabolizing ability of mutants. Reduce the possibility for people taking drugs that they can not metabolize, therefore reduce the rate of adverse drug reactions, and eventually establish a platform of personalized drugs to largely benefit human health.     

Molecular simulation study of the binding mechanism of [α-PTi<Subscript>2</Subscript>W<Subscript>10</Subscript>O<Subscript>40</Subscript>]<Superscript>7−</Superscript> for its promising broad-spectrum inhibitory activity to FluV-A neuraminidase

Polyoxometalate (POM) has promising antiviral activities. It shows broad-spectrum inhibiting ability, high efficiency, and low tox-icity. Experimental assays show that titanium containing polyoxotungstates have anti-influenza-virus activity. In this paper, the bind-ing mechanisms of five isomers of di-Ti-substituted polyoxotungstate, [α-1,2-PTi₂W₁₀O₄₀]^7– (α-1,2), [α-1,6-PTi₂W₁₀O₄₀]^7– (α-1,6), [α-1,5-PTi₂W₁₀O₄₀]^7– (α-1,5), [α-1,4-PTi₂W₁₀O₄₀]^7– (α-1,4) and [α-1,11-PTi₂W₁₀O₄₀]^7– (α-1,11), to five subtypes of influenza virus A neuraminidase (FluV-A NA) were investigated in the context of aqueous solution by using molecular docking and molecular dynamics studies. The results show that the isomer α-1,2 is superior to other isomers as a potential inhibitor to neuraminidase. The positively charged arginine residues around the active site of NA could be induced by negatively charged POM to adapt themselves and could form salt bridge interactions and hydrogen bond interactions with POM. The binding free energies of POM/NA complexes range from –5.36 to –8.31 kcal mol^–1. The electrostatic interactions are found to be the driving force during the binding process of POM to NA. The conformational analysis shows that POM tends to bind primarily with N1 and N8 at the edge of the active pocket, which causes the conformational change of the pincers structure comprising residue 347 and loop 150. Whereas, the active pockets of N2, N9 and N4 are found to be more spacious, which allows POM to enter into the active pockets directly and anchor there firmly. This study shows that negatively charged ligand as POM could induce the reorganization of the active site of NA and highlights POM as a promising inhibitor to NA despite the ever increasing mutants of NA.     

基于 NiTi 温敏形状记忆纳米结构调控的润湿性研究

NiTi 合金是常见的形状记忆合金,有着良好的形状记忆效应、超弹性、耐腐蚀性和生物相容性,在生物医疗、 航空航天和微机电等领域有着广泛的应用。 目的 研究 NiTi 合金表面不同纳米级结构的润湿性能,改善 NiTi 合金 在工作环境下的磨损情况,提高 NiTi 合金的使用寿命。 方法 使用分子动力学方法模拟周期性边界条件下 NiTi 合 金的形状记忆效应,研究在不同温度下 NiTi 合金原子的微观结构演化;同时基于 NiTi 合金温度响应下不同的微观 结构,建立液滴静态接触角仿真,研究 NiTi 合金表面在不同微观结构下的润湿性能。 结果 发现 NiTi 合金在不同温 度响应下发生相变,从而使 NiTi 合金的表面原子排列发生改变,展示了温度诱发 NiTi 合金的相变和逆相变行为以 及在原子尺度下的微观结构演化,再以不同温度响应下发生相变和逆相变的 NiTi 合金表面作为基底,发现其表面 的润湿性也发生了改变和恢复。 结论 NiTi 合金随温度响应发生相变,微观结构发生改变,其表面的润湿性能也发 生改变;而且 NiTi 合金随温度逆相变,微观结构恢复到初始状态,其表面润湿性也能随之恢复到初始状态;NiTi 合 金在相变过程中的奥氏体和马氏体含量会影响 NiTi 合金表面润湿性能,因此能够通过温度进行 NiTi 合金表面在 微观结构下润湿性的自适应调控。     

基于分子轨道隐式溶剂H2O下苏氨酸的电荷转移

基于分子轨道（MO）和自然跃迁轨道（NTO）成分计算分子片段间的电荷转移. 先用密度泛函理论(DFT)中的CAM-B3LYP方法, 在6-31G(d)基组水平上优化隐式溶剂H₂O下苏氨酸（Thr）分子的几何构型，  再在相同理论方法下进行含时密度泛函理论(TDDFT)的电子激发计算, 给出隐式溶剂H₂O下Thr分子体系电子激发过程中片段间电荷转移特征的对比结果. 结果表明： 在S1~S5激发态中, 仅S2中有一对MO32→MO33跃迁轨道占绝对优势, 可通过分析该轨道的成分讨论电荷转移； 其他激发态可通过NTO分析方法讨论电荷转移； S0向激发态S1,S3和S4电荷转移的主要贡献为NTO32→NTO33轨道, 与Hirshfeld和Becke方法的定性结果一致, 定量结果略有差别.