【作者】 刘鹏；

【导师】 蔡文生；

【作者基本信息】 南开大学 ， 分析化学， 2013， 博士

【摘要】 轮烷是一类新兴的超分子复合物,具有多个稳定构象和一个穿梭过程,使其在制备分子器件方面有着巨大的应用价值。然而,轮烷分子体积小柔性大,很难通过实验方法研究轮烷的结构细节。结构细节的缺失极大的阻碍了对现有器件的认识和新型器件的设计。因此,本论文采用理论模拟方法从微观角度分别研究两种轮烷的稳定构象和穿梭过程,旨在为现有分子器件的工作机理提供理论解释,同时为新型分子器件的结构设计提供理论指导。主要内容如下：(1)分子项链是一种[n]轮烷,由n-1个环糊精包结在一个二硝基苯封端的聚乙二醇链上所形成,在药物/基因载体领域内有潜在的应用价值。采用理论模拟方法探索了分子项链的稳定构象。首先,通过分子动力学模拟结合自由能计算方法研究了三种准[3]轮烷的形成过程及稳定构象；其次,通过格点链Monte Carlo方法将对稳定构象的研究从准[3]轮烷推广到准[n]轮烷；最后,得到分子项链的稳定构象、形成机理和关键作用,丰富了对分子项链的认识。为开发基于分子项链的药物/基因载体提供理论基础,同时为探索其它化学和生物体系的自组装现象提供了一种新的研究方法。(2)轮烷是由一个环状分子包结在一个两端封端的线状分子上形成的超分子复合物。线状分子内有多个可以和环状分子特异性结合的位点。通过外界刺激,环状分子在结合位点间的转移便形成轮烷的穿梭。穿梭运动是轮烷诸多应用的基础。通过理论模拟的方法研究了一种轮烷的穿梭运动。首先,优化了体系中三个分子片段的缺失参数；其次,使用分子动力学模拟结合自由能计算方法得到轮烷穿梭的自由能曲线,得到了能垒高度及穿梭时间,解释了实验现象；最后,通过分解自由能曲线,得到了轮烷穿梭的机理及驱动力,扩展了对实验现象的认识,并为进一步研究溶剂驱动的穿梭运动奠定了良好基础。(3)溶剂驱动穿梭的轮烷可用于制备药物载体。该类载体能有效提高药物分子的穿膜效率并显著降低肿瘤细胞的抗药性。通过分子动力学模拟结合自由能计算方法研究了一种溶剂和温度驱动穿梭的轮烷分子,研究轮烷分子在不同溶剂和温度下的穿梭过程,得到了表征轮烷穿梭的自由能曲线。随后,通过自由能曲线分解,得到溶剂和温度对轮烷穿梭的驱动机理,合理的解释了实验现象,扩展了对轮烷穿梭的认识,并为进一步研究基于轮烷的药物载体奠定了良好基础。(4)自由能微扰方法(free energy perturbation, FEP)是一种广泛使用的自由能计算方法,可以直接计算某个反应初始态间的自由能差而不必知晓具体的反应过程。使用Tcl／Tk语言编写了第一种针对FEP计算的分析插件,parseFEP。该插件包含方差计算、熵焓计算、双向模拟整合等多项数据处理功能,可以简化对计算结果的分析。其包含的图形显示功能可以实现计算结果的可视化。通过对冠醚与钾离子结合以及乙醇分子、甲基咪唑水化的研究验证了该插件的实用性。可见,parseFEP为分析FEP的计算结果提供了一个强有力的工具,且为FEP方法的进一步推广奠定了良好基础。更多还原

【Abstract】 Rotaxanes are mechanically interlocked molecular complexes. They have two or more stable conformations. The shuttling processes can transform from one conformation to another one. Those unique properties make rotaxanes promising candidates ranging from molecular devices to drug carriers. However, incomplete knowledge about those properties of rotaxanes blocks their further improvements. In this dissertation, stable conformations and shuttling processes of two rotaxanes were investigated with the aid of molecular dynamics simulations and free energy calculations to shed lights on key factors contributed to stable conformations and driving forces underlying shuttling processes. The main contents of the present dissertation include:(1) Molecular necklaces are one kind of [n]rotaxanes, which are formed by n-1a-cyclodextrins (a-CDs) threaded onto one poly(ethylene glycol) chain. Those necklaces have been envisioned to hold great promise as drug carriers and gene vectors. Their function depends intimately on their stable conformations. Here, molecular dynamics simulations, free-energy calculations, and lattice chain Monte Carlo simulations have been applied to explore this CD-based rotaxane. Stable conformations have been obtained. The results are consistent with experiments. Meanwhile, the methods used in this chapter are expected to help investigate other one dimentional chemical or biological self-assembly processes.(2) Rotaxanes are composed by a linear molecule with stoppers at both termini and a macrocycle, i.e.,α-CD, threaded onto the latter. This macrocycle can shuttle between two or more stations connected by linkers under external stimuli. Here, molecular dynamics simulations combined with free-energy calculations have been applied to investigate a CD-based rotaxane. The free-energy profile characterizing the shuttling process of the CD along the molecular thread was determined and partitioned into tcontributions of different nature. The underlying molecular mechanism of the shuttling process has been deciphered. The present results rationalize experimental observations, and provide the theoretical basis for the investigataion of solvent-driven shuttling processes.(3) The shuttling process of rotaxanes driven by solvents can greatly facilitate translocation of drugs across the plasma membrane. Here, molecular dynamics simulations combined with free-energy calculations have been applied to investigate a rotaxane drivened by solvent and temperature. The free-energy profiles delineating the shuttling processes of this rotaxane in different environments have been drawn. The underlying shuttling mechanism and driving force were obtained. The results match well with experimental measures, and pave the way for further investigation aimed at understanding the working mechanism of rotaxane-based drug carriers.(4) Free-energy perturbation (FEP) is one of the most commonly chosen approaches for tackling transformations of a chemical process between two or more thermodynamic states. To augment the accuracy, the precision, and, hence, the reliability of these calculations, a number of good practices have been established. Here, a plugin, coined ParseFEP, was proposed to follow these prescriptions in a user-friendly environment. Written as a Tcl plugin, it allows FEP calculations carried out using the popular molecular-dynamics package NAMD to be analyzed seamlessly within the visualization platform VMD. The potential of this plugin is probed through a number of illustrative examples, which demonstrate cogently how pathological cases, often related to convergence issues, can be detected and remedied by means of a pictorial approach.更多还原