Indolicidin及其類似物與微脂粒交互作用之熱力學研究; Thermodynamics of the interaction of indolicidin analogs with SUVs

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Title:	Indolicidin及其類似物與微脂粒交互作用之熱力學研究;Thermodynamics of the interaction of indolicidin analogs with SUVs
Authors:	張立煒;Li-wei Chang
Contributors:	化學工程與材料工程研究所
Keywords:	熱力學;鹼性抗生胜肽;微脂粒;indolicidin;SUV;equilibrium dialysis;thermodynamics;antimicrobial peptides
Date:	2010-07-27
Issue Date:	2010-12-08 13:37:00 (UTC+8)
Publisher:	國立中央大學
Abstract:	鹼性抗生胜肽Indolicidin(IL)因其具有廣效且迅速的抗菌性，同時不易造成微生物的抗藥性，因此近年來被廣泛的研究以期能成為新一代的抗生藥物。然而，IL因對紅血球有溶血活性而限制了其進一步的發展。本實驗室利用分子動態模擬，設計了其低溶血性的類似物ILK7、ILF89和ILK7F89，而這些類似物也各自展現出不同強弱的抗菌性。本研究主要是從熱力學的角度，探討IL及其類似物與仿紅血球、仿細菌生物膜系統微脂粒(small unilamellar vesicle，SUV)間的交互作用，進而觀察其不同溶菌與溶血性的根源。首先，我們利用平衡透析的實驗方法，獲得作用達平衡時胜肽吸附在微脂粒上的吸附量，並由胜肽初始濃度的不同進一步獲得其恆溫吸附曲線。由於傳統用來描述蛋白質分子吸附於基質上的Langmuir adsorption model無法恰當的描述IL及其類似物與磷脂膜之吸附作用，於是本研究提出了一個新的吸附模式：Two-site adsorption model。此吸附模式主要將IL及其類似物自我聚集(self-aggregate)成寡聚體之現象考量進吸附反應當中，而此模式也精確的模擬了胜肽分子於兩種不同生物膜之吸附作用。接下來本研究利用van’t Hoff方程式的二次式關係式來求得反應的熱力學參數，並進一步的由熱力學參數分析IL及其類似物與仿生物細胞膜之吸附作用。從熱力學參數的分析我們可以得知：(1) IL及其類似物於液相中的寡聚現象主要是疏水力作用的一種亂度趨動(Entropy driven)之反應。(2) 無論與細菌細胞膜或紅血球細胞膜作用，IL及其類似物都傾向於以聚集體的方式吸附於其上。(3) 無論以單體形式或以聚集體形式吸附，IL及其類似物對生物膜的作用力大小都與其生物活性強弱呈現相當大的相關性。(4)藉由比較單體與聚集體之熱力學參數，可得知聚集體因為其吸附於膜上後可能產生分散現象，而造成細胞膜較大的擾亂，所以其吸附焓及亂度都較單體來的大。綜合來看，IL及其類似物無論以單體或聚集體吸附，其與細胞膜之親和性皆與生物活性呈現正相關，又吸附作用中其傾向以聚集體吸附的程度又大於單體吸附，所以可知IL及其類似物之寡聚現象對其生物活性的影響相當重要。 Cationic antimicrobial peptide Indolicidin(IL) are beimg increasingly recognized as potential candidates for antibacterial drugs in the face of the rapidly emerging bacterial resistance to conventional antibiotics in recent years.However,its hemolytic activity limit its application. We design it’s anlogoues ILK7, ILF89 and ILK7F89 according to the results of molecular dynamics simulation in order to reduce the hemolytic activity but remain the antimicrobial activity. Understand the interaction between peptides and cell membrane may help us to reach our goal. In this study, we want to investigate thermodynamics of the interaction between IL-analogues and lipid bilayers. Because of the less accuracy of Langmuir adsorption model, we proposed a new adsorption model: Two-site sdsorption model to simulate the isothermal adsorption curve obtained from equlilibrium dialysis experiment . The difference between the two models is the self-aggregate phenomenom of IL-anlogues is taken into consideration. The results of using Two-site adsorption model simulate the isothermal adsorption curve is quite well. Then we use van’t Hoff quadratic equation to get the thermodynamic parameters of the peptide-membrane interaction. Through analysis of the thermodynamic parameters we could understand that (1) the self-aggregation of IL-anlogues is driven by entropy. (2) IL and its analogues tend to adsorb to both bacterial and mammalian red blood cell membrane in the aggregated form.(3) The biological activities of IL-analogues are well correlated with its binding affinity to lipid bilayer.(4) Because of the membrane interruption and membrane dispersion of peptides, the enthalpy and entropy change of aggregate adsorption are more than monomer adsorption. As a result, self-aggregation phonomenom is a important factor to affect its biological activity.
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