基于环糊精构筑的分子器件的模拟研究

Due to their potential applications in drug delivery and miniaturization of electronic devices, more and more molecular devices have been designed and synthesized, along with a series of research works focusing on their properties. More and more attention, either scientific or commercial, has been drawn to this field. Among thousands of kinds of molecular devices, the supramolecular system made of rotaxane-like molecular shuttles has a very promising prospect. The ring-like molecule can shuttle between different stable stations by controlling the environmental conditions. Besides, molecular pumps whichch are able to convert molecule recognition energy, and molecular reels that can twist or curl, have shown very fascinating specialties in controlling the movement of molecules. These molecular devices are expected to be widely applied in molecular switches, molecular logic gates and drug delivery, as a result of which, great interest has been devoted to this kind of research. The present project, aimed at a deep insight view into the cyclodextrin-based molecular devices, will give light upon their different driving patterns (i.e. solvent-driven, temperature- and light-driven) within the molecular dynamics framework. In this project, a highly efficient free energy calculation method, Adaptive Biasing Force, will be employed to estimate the free energy changes associated with the related motion processes, and the results will be compared with experiments. Emphasis will be given to inter- and intra-molecular interactions, driving forces, and the mechanism of stabilization. Based on the analysis of the results, further progress will be made on the mechanism of energy transition and response to environmental conditions. In addition, the transmembrane process of a solvent-driven rotaxane at the water-membrane interface will be investigated. The effect of the shuttling of the cyclic molecule in the rotaxane on the transmembrane process will be explored. The results will lay a theoretical foundation for the design of new drug carriers.

由于在分子开关、分子逻辑门和药物输送等领域有着潜在的应用价值，分子器件的设计、合成以及性质的研究已成为最受瞩目的研究领域之一。具有轮烷典型结构特征的分子梭是构成分子器件的重要超分子体系。可通过控制外界环境的变化，使环状分子在不同位置间移动；另外，能够转换分子识别能的分子泵和能够卷曲的分子卷轴也展现出新颖的可控调节分子运动的魅力。本项目将利用分子动力学模拟方法对基于环糊精构筑的多种不同驱动模式（溶剂、温度和光）的分子器件进行研究，模拟分子的运动过程。利用高效的自由能计算方法，计算相应运动过程的自由能变化，并与实验结果进行比较。旨在揭示分子器件中所涉及的分子间相互作用、驱动力和形成机制；进一步对体系中能量传递机理以及对外界条件的响应机理进行研究。另外，将对一种溶剂驱动的轮烷在水-细胞膜界面穿越细胞膜的过程进行研究，探索轮烷中环糊精的穿梭行为对轮烷跨膜过程的影响，为设计新型药物载体提供理论依据。

改进了传统的自适应偏置力（ABF）自由能计算方法，实现了动态扩展ABF（on-the-fly eABF）算法，并在此基础上与广义ABF结合，提出了扩展广义ABF方法（egABF），极大扩大了传统ABF方法的应用范围和效率。将分子动力学模拟结合自由能计算方法用于基于环糊精构筑的药物载体捕获和输送药物的机理研究。进一步，用于多种基于环糊精等大环分子构筑的分子器件/机器在不同外部刺激下的自组装和运动机理的研究，揭示了分子器件中所涉及的分子间相互作用、驱动力和形成机制。另外，对分子机器中相互耦合的多种运动，如旋转、穿梭、翻转和构象变化等进行了深入研究：由于各种运动间高度耦合，使得计算运动过程的自由能变化变得十分复杂，研究结果表明，本项目提出的方法能够应用于探索具有挑战性的多维自由能面。本项研究的科学意义在于：所提出的方法以及所就的理论框架，可用于揭示分子器件/机器中所涉及的分子间相互作用、驱动力和形成机制，并有望用于计算机辅助分子器件/机器设计。