降钙素自组装机理研究
发布时间：2018-11-04 17:05
【摘要】：降钙素是一类对生物机体有重要作用的肽类激素,可以作为许多疾病如高血钙症、骨质疏松症、Paget病等的治疗药物。由于实验上发现它能够自组装成纳米粒子,而纳米粒子在药物缓释载体方面有重要的应用,而且由于降钙素本身是多肽,生物相容性好;并且降钙素本身也可以作为药物。基于以上的理由,我们有必要对它的自组装过程的机制进行深入的研究。实验上的发现还包括二肽和降钙素能一起自组装成纳米粒子,并且能改变纳米粒子的外部形态;在只含降钙素的体系中纳米粒子呈现成杆状,而和二肽一起自组装时纳米粒子为粒子状。本文采用动力学模拟、分子对接等手段来研究它们的机制,以期对以后合成药物载体提供指导和建议。本文采用循序渐进的方法来研究它们的机制;先利用分子对接、动力学模拟以及能量计算等手段来研究单个降钙素和单个降钙素之间以及单个降钙素和单个二肽之间的结合机制。我们通过对能量的分析发现,降钙素之间主要是通过范德华作用力来结合的初步结论。而通过对不同种类的降钙素二肽体系结果进行比较可以发现,二降钙素和二肽分子的结合过程中,静电作用起到了关键性的作用。之后我们通过构建相对较小的降钙素和二肽DF体系来进行全原子的动力学模拟,以期得到降钙素二肽DF一起组装时的机制。我们通对降钙素的二级结构的统计,降钙素表面静电势的计算,以及结合到降钙素上的二肽的数目的统计来对自组装过程机制进行描述和推断。并对降钙素纳米粒子的形态转变进行了理论上的解释。结论是:自组装过程以降钙素为主导,二肽则在不断地寻找合适的位置结合到降钙素上去,对于二肽DF,它主要是以静电作用结合到降钙素上去的。最后我们利用粗粒度模型来对自组装全过程进行模拟,设计了几种不同性质的二肽来和降钙素一起进行自组装。通过对轨迹的对比我们发现具有强疏水作用性质的残基能很好地和降钙素一起进行自组装。这说明强的疏水作用在自组装过程中也起到了关键性的作用。
[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.
【学位授予单位】：电子科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R3411
本文编号：2310553
[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.
【学位授予单位】：电子科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R3411
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