【摘要】：降鈣素是一類對生物機體有重要作用的肽類激素,可以作為許多疾病如高血鈣癥、骨質疏松癥、Paget病等的治療藥物。由于實驗上發(fā)現(xiàn)它能夠自組裝成納米粒子,而納米粒子在藥物緩釋載體方面有重要的應用,而且由于降鈣素本身是多肽,生物相容性好;并且降鈣素本身也可以作為藥物�；谝陨系睦碛�,我們有必要對它的自組裝過程的機制進行深入的研究。實驗上的發(fā)現(xiàn)還包括二肽和降鈣素能一起自組裝成納米粒子,并且能改變納米粒子的外部形態(tài);在只含降鈣素的體系中納米粒子呈現(xiàn)成桿狀,而和二肽一起自組裝時納米粒子為粒子狀。本文采用動力學模擬、分子對接等手段來研究它們的機制,以期對以后合成藥物載體提供指導和建議。本文采用循序漸進的方法來研究它們的機制;先利用分子對接、動力學模擬以及能量計算等手段來研究單個降鈣素和單個降鈣素之間以及單個降鈣素和單個二肽之間的結合機制。我們通過對能量的分析發(fā)現(xiàn),降鈣素之間主要是通過范德華作用力來結合的初步結論。而通過對不同種類的降鈣素二肽體系結果進行比較可以發(fā)現(xiàn),二降鈣素和二肽分子的結合過程中,靜電作用起到了關鍵性的作用。之后我們通過構建相對較小的降鈣素和二肽DF體系來進行全原子的動力學模擬,以期得到降鈣素二肽DF一起組裝時的機制。我們通對降鈣素的二級結構的統(tǒng)計,降鈣素表面靜電勢的計算,以及結合到降鈣素上的二肽的數(shù)目的統(tǒng)計來對自組裝過程機制進行描述和推斷。并對降鈣素納米粒子的形態(tài)轉變進行了理論上的解釋。結論是:自組裝過程以降鈣素為主導,二肽則在不斷地尋找合適的位置結合到降鈣素上去,對于二肽DF,它主要是以靜電作用結合到降鈣素上去的。最后我們利用粗粒度模型來對自組裝全過程進行模擬,設計了幾種不同性質的二肽來和降鈣素一起進行自組裝。通過對軌跡的對比我們發(fā)現(xiàn)具有強疏水作用性質的殘基能很好地和降鈣素一起進行自組裝。這說明強的疏水作用在自組裝過程中也起到了關鍵性的作用。
[Abstract]:Calcitonin is a kind of peptide hormone which plays an important role in organism. It can be used as a treatment for many diseases such as hypercalcemia, osteoporosis, Paget's disease and so on. It is found that it can self-assemble into nanoparticles, and nanoparticles have important applications in drug delivery support, and because calcitonin itself is a polypeptide, it has good biocompatibility, and calcitonin itself can also be used as a drug. For these reasons, it is necessary to study the mechanism of self-assembly. The experimental findings include that dipeptides and calcitonin can self-assemble into nanoparticles together, and can change the external morphology of nanoparticles; In the system containing calcitonin only, the nanocrystalline particles take on the shape of rods, while the nanoparticles are particles when self-assembled with dipeptide. In this paper, kinetic simulation and molecular docking were used to study their mechanism in order to provide guidance and advice for the synthesis of drug carriers in the future. In this paper, a step-by-step approach is adopted to study their mechanisms. The binding mechanism between single calcitonin and single dipeptide was studied by molecular docking kinetic simulation and energy calculation. Our energy analysis shows that calcitonin is mainly bound by van der Waals force. By comparing the results of different calcitonin dipeptide systems, it is found that electrostatic action plays a key role in the binding process of dicalcitonin and dipeptide molecules. Then we construct a relatively small calcitonin and dipeptide DF system to simulate the kinetics of the whole atom in order to obtain the mechanism of calcitonin dipeptide DF assembled together. The secondary structure of calcitonin, the calculation of the surface electrostatic potential of calcitonin and the statistics of the number of dipeptides combined with calcitonin are used to describe and infer the mechanism of the self-assembly process. The morphological transition of calcitonin nanoparticles was explained theoretically. The conclusion is that calcitonin is dominant in the self-assembly process and the dipeptide is constantly searching for a suitable position to bind to the calcitonin. For the dipeptide DF, it is mainly bound to calcitonin by electrostatic action. Finally, we simulate the whole process of self-assembly by coarse-grained model, and design several dipeptides with different properties to self-assemble with calcitonin. By contrasting the trajectories, we find that the residues with strong hydrophobicity can self-assemble well with calcitonin. This indicates that strong hydrophobic action also plays a key role in self-assembly process.
【學位授予單位】：電子科技大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R3411

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本文編號：2310553