本文選題：磷脂雙層膜　切入點：離子通道　出處：《吉林大學(xué)》2016年博士論文

【摘要】：所有的細(xì)胞都有細(xì)胞膜和跨膜離子轉(zhuǎn)運系統(tǒng)的存在。生命需要特殊的密閉環(huán)境,但是也需要和外面的世界進(jìn)行不斷的物質(zhì)交換。這種交換是高效的、選擇性的,同時會接受生命體的調(diào)控,并會對整個生命體的狀態(tài)產(chǎn)生影響。因此離子、水和糖等小分子的跨膜轉(zhuǎn)運活動及其分子基礎(chǔ)對于生命的意義非同一般。有了這樣一套系統(tǒng),生命體才能進(jìn)行正常的新陳代謝和各種生理活動,包括心跳、味覺、觸覺、神經(jīng)沖動等等。從1982年第一個人工離子通道化合物被報道迄今為止的34年間,化學(xué)家進(jìn)行了不斷的努力試圖構(gòu)建可以與大自然相媲美的跨膜離子轉(zhuǎn)運系統(tǒng)。從最早的修飾環(huán)糊精到最近報道的折疊體衍生物,從接近天然的多肽分子到無機(jī)的碳納米管,從單碳原子的氣態(tài)氟化小分子到復(fù)雜的DNA機(jī)器,各種各樣的結(jié)構(gòu)被用于實現(xiàn)細(xì)胞膜滲透性的改變。不僅僅是由于物質(zhì)跨膜運輸系統(tǒng)對于生命的重要性,更是為了能向大自然經(jīng)過億萬年進(jìn)化后所留下的這一最為精妙和高效的體系進(jìn)行學(xué)習(xí),了解其中的規(guī)律和奧妙。得益于科學(xué)的不斷發(fā)展,各種可以應(yīng)用于該領(lǐng)域的表征和證明的手段日益成熟和多樣,使得我們可以對人工的跨膜體系和天然蛋白質(zhì)系統(tǒng)進(jìn)行細(xì)致入微的探究和分析。而且隨著研究的深入,越來越多的人工系統(tǒng)已經(jīng)在體內(nèi)和體外的生物實驗中表現(xiàn)出良好的效果,為人們將來進(jìn)一步開發(fā)需要的藥物傳遞系統(tǒng)、離子通道病的治療和臨床工具提供了希望。除此之外,經(jīng)過基因過程和化學(xué)修飾的半人工系統(tǒng)已經(jīng)在DNA測序、水凈化膜等方面取得了相當(dāng)?shù)倪M(jìn)步和成果,有些成功的產(chǎn)品已經(jīng)被開發(fā)出來。雖然今天的人工離子跨膜運輸體系面臨著巨大的挑戰(zhàn),但是也充滿著機(jī)遇。首先,目前大多數(shù)人工的離子跨膜轉(zhuǎn)運體系無論從通道效率還是離子選擇性上都還無法與天然系統(tǒng)相匹敵。而對于實際應(yīng)用來說,最小的劑量和最高的效率始終是一個重要的指標(biāo)。其次,具有“活的”生命體特征的離子通道,也即可以對外界刺激響應(yīng)的智能型體系的構(gòu)建仍然處于初級階段。構(gòu)建智能型跨膜離子轉(zhuǎn)運體系是向大自然學(xué)習(xí)的一個重要參數(shù)和終極目標(biāo)。因此,我們立足于使用簡單、成本低、耗時少的化學(xué)合成手段,通過理性設(shè)計,得到了三種不同的離子跨膜傳輸系統(tǒng)。在這些系統(tǒng)中,我們分別探討和研究了追求高的離子轉(zhuǎn)運效率、智能性和適用性、離子選擇性等不同特性時的一些規(guī)律和設(shè)計原則。1.我們在前人三腳架型離子轉(zhuǎn)運體研究的基礎(chǔ)上,以含不同氧族元素的雙胺基小分子作為骨架,以硫脲基作為結(jié)合陰離子的氫鍵給體,合成了9種不同的簡單小分子離子轉(zhuǎn)運體,試圖尋找高效的兩腳架型離子轉(zhuǎn)運體,并探究優(yōu)化其效率的方法。我們從陰離子結(jié)合常數(shù)、分子脂溶性以及它們轉(zhuǎn)運體的離子傳輸效率的關(guān)系進(jìn)行了詳細(xì)的測試和分析,發(fā)現(xiàn)不同的氧族元素和不同的芳香取代基對于轉(zhuǎn)運體的效率有著清晰而又不同的影響。而且,從這9種分子中,我們得到了一種效率極高的陰離子轉(zhuǎn)運體,其活性幾乎已經(jīng)可以達(dá)到天然產(chǎn)物的水平。2.我們利用已經(jīng)得到的含硒雙腳架型離子轉(zhuǎn)運體構(gòu)建了智能型納米粒子離子轉(zhuǎn)運系統(tǒng)。這樣的體系可以對與生理活動密切相關(guān)的含巰基分子(例如谷胱甘肽、半胱氨酸等)做出響應(yīng)。在納米粒子的狀態(tài)下,離子轉(zhuǎn)運體由于淬滅效應(yīng)效應(yīng)而失活。而這種納米粒子因為較小的半徑可以在高濃度時分散在水中,解決了其轉(zhuǎn)運體分子水溶性差的問題。在利用巰基對納米粒子進(jìn)行激活時,由于體系的超敏感性,我們可以對體系進(jìn)行多種方式的定量的調(diào)控。最終,我們還嘗試用這樣的體系對巰基進(jìn)行超靈敏的監(jiān)測,發(fā)現(xiàn)其檢測限可以達(dá)到納摩爾級別。3.我們利用納米級的具有清晰的精細(xì)螺旋結(jié)構(gòu)的聚合物構(gòu)建了一個跨膜通道體系。這一體系由于螺旋聚合物堅固剛性的骨架、合適的可以匹配磷脂層結(jié)構(gòu)的尺寸和多重柔性長鏈,而具有極高的通道穩(wěn)定性和離子傳輸效率。這一通道還有特定的陽離子選擇性和水分子傳輸?shù)哪芰�。通過進(jìn)一步比較不同長度的螺旋聚合物通道在離子選擇性、單通道壽命和電導(dǎo)等性質(zhì)方面的不同點和相似點,我們還發(fā)現(xiàn)這樣的通道體系可以作為研究天然通道蛋白體系的模型和工具。這些新穎的跨膜離子轉(zhuǎn)運體系具有各自不同的特色和其獨特的優(yōu)點,因此有著巨大的潛力和應(yīng)用價值,可以在不同的場景下發(fā)揮獨特的生物功能。
[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.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：Q25;O631

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