药物小分子穿越磷脂双层膜输运过程中的时滞效应

本文基于扩散动力学,建立了一种新的药物小分子穿越磷脂双层膜输运的理论模型,研究药物小分子穿越磷脂双层膜输运的动态过程,考察药物小分子跨膜输运过程中的时间延迟(时滞)效应。研究发现,药物小分子在数分钟内穿越磷脂双层膜各区域进入细胞,由于时滞效应,穿膜过程呈现了周期性演化特性。当药物小分子数量增加到一定程度,磷脂分子层会出现微小孔,让积累的药物小分子快速通过。通过分析模型中各参数的敏感性,我们还发现,药物小分子在磷脂双层膜内不同区域的扩散特性,以及输运过程的时滞性,都会对药物小分子穿越磷脂双层膜的动力学有较大程度的影响。理论结果符合模拟、实验观测,进一步深刻揭示了药物小分子穿越磷脂双层膜的穿膜特性,可为设计确切的疗法药物提供必要的参考和新方案。     

不同类型细胞穿膜肽二级结构特征研究

细胞穿膜肽是一类能以受体依赖或非受体依赖方式介导胞吞作用的小分子短肽,能够携带不同分子穿过细胞膜,这一特性使细胞穿膜肽成为一种有效的运输载体,为药物靶向治疗提供了新希望.本文从生物信息角度针对不同长度区间、运输不同类型分子细胞穿膜肽之间的异同二级结构特征进行了系统研究,同时进一步对不同穿膜方式对应的细胞穿膜肽二级结构特征进行了对比研究,结果表明不同类型细胞穿膜肽之间在二级结构组成上具有不同程度差异特征,为今后揭示细胞穿膜肽相关分子结构机制奠定可靠的理论基础.     

靶向肿瘤因子c-MYC基因启动区G4-DNA的小分子药物设计及核磁共振研究进展

肿瘤基因MYC在人类70%癌细胞中高表达,抑制其转录是治疗肿瘤的有效手段.c-MYC启动子区P1近端的核酸酶超敏元件Ⅲ₁(NHE Ⅲ₁)控制MYC基因近90%的转录激活.NHE Ⅲ₁区域富含碱基G序列并且形成G-四链体(G4),调控c-MYC基因转录,是抗肿瘤药物靶标.但G4-DNA和G4-RNA的三维结构高度相似,小分子与其他G4(如端粒G4、mRNA G4、c-Kit G4等)的非特异性作用会产生小分子药物“脱靶”效应,同时小分子药物会诱导其他G4形成从而干扰正常细胞的功能,造成靶向c-MYC G4抗癌药物设计困难.本文综述了近些年靶向肿瘤因子c-MYC G4-DNA的小分子药物研究进展,及核磁共振(NMR)技术在G4-DNA和G4-RNA结构确定中的作用,为靶向c-MYC G4-DNA的小分子药物设计等相关研究工作提供参考.     

分子的位置取向对分子器件电输运特性的影响

以1,4-二硫酚(DTB)分子为研究对象，利用第一性原理计算方法和非平衡格林函数理论，研究了分子的位置取向对分子电子结构以及分子结电输运性质的影响.计算结果表明，分子位置取向的改变会影响分子的电子结构，从而影响分子体系的电输运特性，扩展分子的平衡态不是电子输运的最佳状态，适当调节分子的位置取向可以提高分子的电输运特性. 关键词： 位置取向 电子输运 分子电子学     

电极距离对分子器件电输运特性的影响

以4,4′_二巯基联苯分子为研究对象，利用从头计算方法和弹性散射格林函数理论，研究了两个电极之间的距离对分子几何结构和电子结构以及该分子结电输运性质的影响. 计算结果表明，电极距离的不同会改变分子的几何结构和电子结构，从而影响分子体系的电输运特性. 扩展分子的平衡状态不是电子输运的最佳状态，适当调整两个电极之间距离可以改善分子的电输运特性. 关键词： 电极距离 伏 安特性 分子电子学     

官能团对分子器件电输运特性的影响

以4,4′-二巯基联苯分子为研究对象,利用第一性原理计算方法和非平衡格林函数理论,研究了官能团氨基和硝基对分子的电子结构以及分子结电输运性质的影响. 计算结果表明,在分子的不同位置添加同一类官能团氨基会使分子的电子结构发生变化,从而影响分子结的电输运性质. 而在分子的同一位置添加不同类型的官能团氨基和硝基则对分子间的相互作用有着显著影响,会使分子发生转动,从而改变分子的几何结构和电子结构,影响分子结的电输运特性. 并且发现随着分子的转动,添加官能团硝基时分子会呈现出记忆功能. 关键词： 官能团 电子输运 分子电子学     

光激发下分子纳米结中电荷输运的振动效应研究

在纳米金属电极和分子组成的分子纳米结中,应用分子振动的简正坐标在弱耦合近似下研究了在光激发作用下电荷的输运过程,并从电离能的角度分析了顺序电荷转移的机理,研究了在光激发条件下分子纳米结的电流-电压特性. 发现分子的振动效应是Franck-Condon阻滞在光激发作用下消失的关键因素,进而在理论上分析了分子的电离能在电荷输运中的作用,同时分析了IVR效应对光激发下分子纳米结中电荷输运的影响. 关键词： Franck-Condon阻滞 振动效应 电流-电压特性     

A-Z-A型石墨烯场效应晶体管吸附 效应的第一性原理研究

利用第一性原理的计算方法, 研究了A-Z-A型GNR-FET的电子结构和输运性质及其分子吸附效应. 得到了以下结论: 纯净的A-Z-A型GNR-FET具有典型的双极型晶体管特性, 吸附分子的存在会使纳米带能隙变小. 对于吸附H, H₂, H₂O, N₂, NO, NO₂, O₂, CO₂和SO₂分子的情况, A-Z-A型GNR-FET仍然保持着场效应晶体管的基本特征, 但吸附不同类型的分子会使GNR-FET的输运特性发生不同程度的改变; 对于吸附OH分子的情况, 输运特性发生了本质的改变, 完全不具有场效应晶体管的特性. 这些研究结果将有助于石墨烯气体探测器的工程实现, 并对应用于不同环境中GNR-FET的设计具有重要指导意义.     

基于三磷酸腺苷调节的分子马达单向能量跃迁模型

分子马达的梯跳运动和在过阻尼溶液中动力学原理尚未揭示清楚, 从分子马达输运特点和实验现象出发, 构建满足朗之万方程的单向能量跃迁模型, 并通过Monte Carlo方法分析了分子马达的随机动力学行为. 结果表明, 在合适的跃迁能量作用下, 分子马达可以利用噪声进行稳定的梯跳运动和有效的输运, 但负载力会减弱分子马达系统的输运能力; 轨道周期势虽影响分子马达速度的大小但不会改变其运动方向, 分子马达运动方向由跃迁能量决定; 另外, 虽然在不同的噪声强度时平均速度不为零, 但是分子马达系统的高效输运对噪声有一定选择性. 关键词： 分子马达 能量跃迁 朗之万方程 噪声强度     

不同取向的1,8-辛二硫醇分子的伏安特性研究

以1,8-辛二硫醇分子为研究对象,在第一性原理基础上,利用弹性散射格林函数方法,研究了1,8-辛二硫醇分子在金原子团簇上不同取向对该分子结电输运特性的影响.计算结果表明,分子与金原子团簇表面之间方位角的不同会导致分子结构、电子结构的改变,从而影响分子体系的电输运特性.当1,8-辛二硫醇分子S-S轴线与金(111)面的法线成25°夹角时,所得到的电流-电压曲线与实验值符合较好.     

Diffusion of gases across lipid membranes with OmpA channel: a molecular dynamics study

Molecular transport across biological membranes occurs in a range of important chemical and biological processes. The biological membrane can usually be modelled as a phospholipid bilayer, but to correctly represent biological transport, the embedded transmembrane proteins must also be included. In previous molecular simulation studies on transport of small gas molecules in dipalmitoylphosphatidylcholine (DPPC) bilayer membrane, a coarse-grained model was used to provide direct insight into collective phenomena in biological membranes. Coarse graining allowed investigation of longer time and length scales by reducing the degrees of freedom and employing suitable potentials. In this work, membranes that include transmembrane proteins are modelled. This allows one to compare the molecular transport across a lipid membrane with and without the assistance of transmembrane channels. Outer membrane protein A (OmpA) – a porin from Escherichia coli with a small pore size – was chosen in this study because its detailed structure is known, it has high stability and is known to form a nonspecific diffusion channel that permits the penetration of various solutes. In this work the pore characteristics and interaction between lipid and protein were investigated and transport of water and other small gas molecules within the channel were studied. The MD simulation results obtained are compared with previous simulation results and available experimental data. The results obtained from this study will lead to better understanding of protein functionality and advance the development of biochips and drug delivery systems.     

Ultrasound-mediated disruption of cell membranes. I. Quantification of molecular uptake and cell viability

Ultrasound-mediated drug delivery is a nonchemical, nonviral, and noninvasive method for targeted transport of drugs and genes into cells. Molecules can be delivered into cells when ultrasound disrupts the cell membrane by a mechanism believed to involve cavitation. This study examined molecular uptake and cell viability in cell suspensions (DU145 prostate cancer and aortic smooth muscle cells) exposed to varying peak negative acoustic pressures (0.6-3.0 MPa), exposure times (120-2000 ms), and pulse lengths (0.02-60 ms) in the presence of Optison (1.7% v/v) contrast agent. With increasing pressure and exposure time, molecular uptake of a marker compound, a calcein, increased and approached equilibrium with the extra cellular solution, while cell viability decreased. Varying pulse length produced no significant effect. All viability and molecular uptake measurements collected over the broad range of ultrasound conditions studied correlated with acoustic energy exposure. This suggests that acoustic energy exposure may be predictive of ultrasound's nonthermal bioeffects.     

水蒸气对二氧化硅膜的影响：吸附性能与渗流效应

研究了在50和90 oC时水蒸气对孔径约为4 ?的二氧化硅膜的吸附性能和渗流效应影响,采用椭圆偏振光谱分析水蒸气的吸附性能,以及测定氦气-H₂O二元混合气体的透过性能. 研究表明水蒸气在二氧化硅膜上的吸附行为符合一阶Langmuir等温线,同时,在H₂O分子存在的条件下,氦气的透过率会急剧下降. 通常,在极小孔内气体分子的传输被认为是不连续的,而是在势能下从一个占有位置跳跃到另外一个空位上. 当在二氧化硅表面的H₂O分子覆盖率上升时,氦气的透过率急剧下降可能与渗流效应有关,其中吸附在二氧化硅表面的H₂O分子阻碍了氦气分子的跳跃.     

Transport of ions and solvent in confined media

A new theoretical approach is used to model the transport properties of a cation-exchange membrane. By using the Navier-Stokes equation related to the Poisson-Boltzmann relation, it is thus possible to determine the solvent velocity in a membrane pore, and the influence of electroosmosis on the transport properties of the polymer. The variation of the transport coefficients with salt concentration in the membrane pore was modeled as for simple electrolytes: taking electrophoretic interactions and relaxation effect into account, we used MSA analytical expressions. We have investigated membrane conductivity and electrophoretic sodium mobility measurements when the membrane was equilibrated with NaCl solution. Good agreement was found between the experimental results and our theoretical model.     

Channel-facilitated molecular transport across membranes: attraction, repulsion, and asymmetry

Transport of molecules across membrane channels is investigated theoretically using exactly solvable discrete stochastic site-binding models. It is shown that the interaction potential between molecules and the channel has a strong effect on translocation dynamics. The presence of attractive binding sites in the pore accelerates the particle current for small concentrations outside the membrane, while for large concentrations, surprisingly, repulsive binding sites yield the most optimal transport. In addition, the asymmetry of the interaction potential also strongly influences the channel transport. The mechanism underlying these phenomena is discussed using the details of particle dynamics at the binding sites.     

VPRBP 蛋白与Abl 激酶诱发、抑制前列腺癌的 一种物理机制

在本文基于Hill动力学与Michaelis-Menten方程,建立理论模型研究VPRBP蛋白与Abl激酶诱发、抑制前列腺癌的一种物理机制.研究发现,DNA损伤使得ATM(共济失调毛细血管扩张症突变)很快激活,并激活上调p53蛋白表达,DNA损伤的后续破坏会在很大程度上通过p53表达上调而被抑制. VPRBP通过上调MDM2蛋白的激活水平,使得p53表达水平异常,进而无法正常抑制前列腺癌的发生发展.通过考察Abl在前列腺癌进程中的作用发现,Abl使得AKT的表达水平下调,由于Abl对AKT的抑制作用,致使在AKT信号通路中MDM2表达水平受到抑制,进而稳定p53表达.由此表明了,过少的Abl对AKT的抑制程度减弱,不仅使得细胞代谢出现紊乱,而且还会促使p53正常的周期表达水平异常,对DNA损伤诱发的肿瘤抑制性减弱,进而促进前列腺癌的发生发展.基于本文模型,可以预测VPRBP与Abl作为诱发、抑制前列腺癌的调节剂对现有和潜在的抗癌治疗较为敏感. VPRBP与Abl在诱发、抑制前列腺癌过程中的时滞效应,导致信号通路中p53与PTEN蓄积量增多、AKT蓄积量减少,以及Plk1周期振荡相位转移...     

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.     

Effect of gas diffusion layer and membrane properties in an annular proton exchange membrane fuel cell

A complete three-dimensional and single phase computational dynamics model for annular proton exchange membrane (PEM) fuel cell is used to investigate the effect of changing gas diffusion layer and membrane properties on the performances, current density and gas concentration. The proposed model is a full cell model, which includes all the parts of the PEM fuel cell, flow channels, gas diffusion electrodes, catalyst layers and the membrane. Coupled transport and electrochemical kinetics equations are solved in a single domain; therefore no interfacial boundary condition is required at the internal boundaries between cell components. This computational fluid dynamics code is used as the direct problem solver, which is used to simulate the two-dimensional mass, momentum and species transport phenomena as well as the electron- and proton-transfer process taking place in a PEMFC that cannot be investigated experimentally. The results show that by increasing the thickness and decreasing the porosity of GDL the performance of the cell enhances that it is different with planner PEM fuel cell. Also the results show that by decreasing the thickness of the membrane the performance of the cell increases.     

模型化研究两细胞间基因、蛋白耦合振荡中的噪声效应

本文基于Hill动力学与Michaelis-Menten方程,建立理论模型研究两细胞间基因、蛋白耦合振荡中的噪声效应.研究发现,在Notch信号通路中,两细胞间基因、蛋白耦合振荡呈现了周期振荡特性,表明了细胞间信号传导的同步振荡特性.“内在”噪声和“外在”噪声对两细胞间基因、蛋白耦合振荡有着不同的作用.内噪声有利于细胞间Notch信号通路中各基因、蛋白表达再次提升.外噪声诱导通路中基因、蛋白的表达水平降低,周期振荡变得阻尼.内、外噪声共同作用不仅可使得基因表达适当并呈现出持续振荡模式,而且还可使得细胞间基因转录合成相应的蛋白过程呈现出持续振荡模式.从而表明了基因表达的内、外噪声共同作用有利于控制细胞间基因激活、蛋白合成保持周期节律性.本文理论结果揭示了内外噪声对细胞间Notch信号通路动力学的一种调控机制,确定了内外噪声各自的调控效应,澄清了内外噪声共同作用调控体系持续周期振荡的物理机制,理论结果符合实验,可为设计阻止Notch体系基因、蛋白变异导致的多种疾病和癌症的通路治疗方案提供理论依据.