人工跨膜离子传输系统的构筑和性质研究

发布时间：2018-03-25 19:55

本文选题：磷脂双层膜　切入点：离子通道　出处：《吉林大学》2016年博士论文

【摘要】：所有的细胞都有细胞膜和跨膜离子转运系统的存在。生命需要特殊的密闭环境,但是也需要和外面的世界进行不断的物质交换。这种交换是高效的、选择性的,同时会接受生命体的调控,并会对整个生命体的状态产生影响。因此离子、水和糖等小分子的跨膜转运活动及其分子基础对于生命的意义非同一般。有了这样一套系统,生命体才能进行正常的新陈代谢和各种生理活动,包括心跳、味觉、触觉、神经冲动等等。从1982年第一个人工离子通道化合物被报道迄今为止的34年间,化学家进行了不断的努力试图构建可以与大自然相媲美的跨膜离子转运系统。从最早的修饰环糊精到最近报道的折叠体衍生物,从接近天然的多肽分子到无机的碳纳米管,从单碳原子的气态氟化小分子到复杂的DNA机器,各种各样的结构被用于实现细胞膜渗透性的改变。不仅仅是由于物质跨膜运输系统对于生命的重要性,更是为了能向大自然经过亿万年进化后所留下的这一最为精妙和高效的体系进行学习,了解其中的规律和奥妙。得益于科学的不断发展,各种可以应用于该领域的表征和证明的手段日益成熟和多样,使得我们可以对人工的跨膜体系和天然蛋白质系统进行细致入微的探究和分析。而且随着研究的深入,越来越多的人工系统已经在体内和体外的生物实验中表现出良好的效果,为人们将来进一步开发需要的药物传递系统、离子通道病的治疗和临床工具提供了希望。除此之外,经过基因过程和化学修饰的半人工系统已经在DNA测序、水净化膜等方面取得了相当的进步和成果,有些成功的产品已经被开发出来。虽然今天的人工离子跨膜运输体系面临着巨大的挑战,但是也充满着机遇。首先,目前大多数人工的离子跨膜转运体系无论从通道效率还是离子选择性上都还无法与天然系统相匹敌。而对于实际应用来说,最小的剂量和最高的效率始终是一个重要的指标。其次,具有“活的”生命体特征的离子通道,也即可以对外界刺激响应的智能型体系的构建仍然处于初级阶段。构建智能型跨膜离子转运体系是向大自然学习的一个重要参数和终极目标。因此,我们立足于使用简单、成本低、耗时少的化学合成手段,通过理性设计,得到了三种不同的离子跨膜传输系统。在这些系统中,我们分别探讨和研究了追求高的离子转运效率、智能性和适用性、离子选择性等不同特性时的一些规律和设计原则。1.我们在前人三脚架型离子转运体研究的基础上,以含不同氧族元素的双胺基小分子作为骨架,以硫脲基作为结合阴离子的氢键给体,合成了9种不同的简单小分子离子转运体,试图寻找高效的两脚架型离子转运体,并探究优化其效率的方法。我们从阴离子结合常数、分子脂溶性以及它们转运体的离子传输效率的关系进行了详细的测试和分析,发现不同的氧族元素和不同的芳香取代基对于转运体的效率有着清晰而又不同的影响。而且,从这9种分子中,我们得到了一种效率极高的阴离子转运体,其活性几乎已经可以达到天然产物的水平。2.我们利用已经得到的含硒双脚架型离子转运体构建了智能型纳米粒子离子转运系统。这样的体系可以对与生理活动密切相关的含巯基分子(例如谷胱甘肽、半胱氨酸等)做出响应。在纳米粒子的状态下,离子转运体由于淬灭效应效应而失活。而这种纳米粒子因为较小的半径可以在高浓度时分散在水中,解决了其转运体分子水溶性差的问题。在利用巯基对纳米粒子进行激活时,由于体系的超敏感性,我们可以对体系进行多种方式的定量的调控。最终,我们还尝试用这样的体系对巯基进行超灵敏的监测,发现其检测限可以达到纳摩尔级别。3.我们利用纳米级的具有清晰的精细螺旋结构的聚合物构建了一个跨膜通道体系。这一体系由于螺旋聚合物坚固刚性的骨架、合适的可以匹配磷脂层结构的尺寸和多重柔性长链,而具有极高的通道稳定性和离子传输效率。这一通道还有特定的阳离子选择性和水分子传输的能力。通过进一步比较不同长度的螺旋聚合物通道在离子选择性、单通道寿命和电导等性质方面的不同点和相似点,我们还发现这样的通道体系可以作为研究天然通道蛋白体系的模型和工具。这些新颖的跨膜离子转运体系具有各自不同的特色和其独特的优点,因此有着巨大的潜力和应用价值,可以在不同的场景下发挥独特的生物功能。
[Abstract]:All cells have a cell membrane and transmembrane ion transport system. Life needs special airtight environment, but also to the outside world and continuous material exchange. This exchange is efficient, selective, and will accept regulation of life, and affect the whole life of the state so the ion transport across the membrane, activity of water and sugar and other small molecules and its molecular basis for the meaning of life is unusual. With such a system, and life to The new supersedes the old. all kinds of physiological activities, including normal heartbeat, taste, touch, nerve impulse and so on. From 1982 the first artificial ion channel compound has been reported so far in 34 years, chemists have made constant effort to construct and can be comparable to the nature of the transmembrane ion transport system. From the earliest modified cyclodextrin to the recently reported fold Laminate derivatives, from natural peptides to inorganic carbon nanotubes to complex DNA machine from gaseous fluorinated small molecule single carbon atoms, various structure is used to implement the cell membrane permeability. The change is not only the result of transmembrane transport system for the importance of life, is to be able to left by nature after millions of years of evolution after the most sophisticated and efficient system for learning, understanding the rules and secret of them. Due to the scientific development, characterization and that can be used in various areas of the increasingly mature and diverse means, we can make the artificial membrane system and natural protein the system of inquiry and nuanced analysis. But with the deepening of research, more and more artificial systems already in biological experiments in vitro and in vivo showed good effect for people Our future needs further development of drug delivery systems, ion channel disease treatment and clinical tools provide hope. Besides, through the semi artificial system process and chemical modification of gene in DNA sequencing, water purification membrane has made considerable progress and achievements, some successful product has been developed. Although today the artificial ion transmembrane transport system is facing a huge challenge, but also full of opportunities. First of all, at present most of the artificial ion transmembrane transport system in terms of channel efficiency or ion selective are unable to compete with natural systems. But in the practical application, the minimum dose and the highest efficiency is always a an important index. Secondly, with the characteristics of ion channel life live ", constructing an intelligent system that can respond to external stimuli is still in the early stage order Section. Construction of intelligent ion transport system is to learn from nature is an important parameter and the ultimate goal. Therefore, we are based on the use of simple, low cost, less time-consuming chemical synthesis methods, through rational design, got three different transmembrane ion transport system. In these systems, we respectively. To investigate and study the ion transport efficiency high, the intelligence and the applicability of different ion selective characteristics of some rules and design principles of.1. in our previous research on the tripod type three transporter, with two amine molecules containing different oxygen group elements as a skeleton with thiourea as anion binding the hydrogen bond donor, 9 kinds of simple small molecular ion transporter synthesis, trying to find a bipod type transporter, and explore the way to optimize its efficiency. We combine constants from the anion, Molecular lipophilic and ion transport efficiency of their transporters were tested and analyzed in detail, found that oxygen group elements with different aromatic substituents have different effects of clarity and efficiency. For the transporter and, from these 9 kinds of molecules, we got a high efficiency anion transporter the selenium bipod type transporter we use has been the level of.2. activity can reach almost natural products to build intelligent nanoparticles ion transport systems. This system can on physical activity and thiol containing molecules are closely related (such as glutathione, cysteine) response. In the nanoparticles state. Ion transporters due to the quenching effect of inactivation. The nanoparticles because of the smaller radius can be in high concentration and dispersed in water, solves the Transport molecules are poorly water soluble. In the nanoparticles activated by thiol, due to the ultra sensitive system, we can carry out a variety of ways of quantitative regulation of the system. Finally, we also try to monitor the ultra sensitive to thiol in this system, the detection limit can reach nanomolar level.3. us the use of nano polymer with fine spiral structure clearly establishes a transmembrane channel system. This system due to strong rigid helical polymer skeleton, the appropriate size can match the phospholipid layer structure and multiple flexible long chain, and has high channel stability and ion transport efficiency. This is a specific channel the cation selective water molecules and the transmission ability. Through the comparison of different length of the helical polymer channel further in ion selective, single channel conductance and life etc. The quality of the differences and similarities, we also found that the channel system can be used as models and tools for the study of natural channel protein system. These novel transmembrane ion transport system with different characteristics and its unique advantages, so it has great potential and application value, can play a unique biological function in different the scene.

【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：Q25;O631

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