本文關(guān)鍵詞： 多肽 定量構(gòu)效關(guān)系 分子設(shè)計 分子動力學(xué) 量子化學(xué)　出處：《重慶大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：多肽作為維持生命體正常運轉(zhuǎn)的關(guān)鍵性物質(zhì)越來越受到人類的關(guān)注，特別是其藥用價值，并且近年來，其在材料方面的應(yīng)用價值也日益凸顯。但是某些多肽其自身的結(jié)構(gòu)與功能還存在一定的缺陷，因此對其結(jié)構(gòu)的優(yōu)化與修飾有助于設(shè)計出更為合理的多肽化合物。 本文運用二維定量構(gòu)效關(guān)系(2D-QSAR)與三維定量構(gòu)效關(guān)系(3D-QSAR)相結(jié)合的方法對阿片肽與淀粉樣肽兩種多肽進行深入研究。主要采用多元線性回歸(MLR)、支持向量機(SVM)、Topomer CoMFA及Topomer Search和分子對接等方法對上述兩種肽的定量構(gòu)效關(guān)系及作用機理全面分析。并在此基礎(chǔ)上，對多肽的結(jié)構(gòu)進行優(yōu)化，設(shè)計出功能更優(yōu)，結(jié)構(gòu)更為合理的新化合物，結(jié)合分子動力學(xué)和量子化學(xué)，對設(shè)計分子進行評估。取得的研究成果如下： ①運用基于R基團的3D Topomer CoMFA建模方法對30個delta阿片六肽進行建模，得到最優(yōu)模型的擬合、交互驗證的復(fù)相關(guān)系數(shù)分別為0.892和0.596。基于所建模型，結(jié)合Topomer Search虛擬篩選方法，設(shè)計215個非天然氨基酸修飾的delta阿片擬肽。經(jīng)預(yù)測，214個分子的活性高于模板分子。運用Surflex-Dock分子對接研究關(guān)鍵位點作用模式與機制，結(jié)合密度泛函理論(DFT)計算相關(guān)位點作用能，，結(jié)果表明delta阿片肽N末端第三個氨基酸對活性具有重要的貢獻。受體的Lys108, Asp128, Tyr129, Lys214, Val217, Val218, Trp284, Leu300, Ile304, Tyr308氨基酸對配體的選擇性及活性具有重要的作用。單點能的計算結(jié)果顯示His278可能與YP型delta阿片肽的活性密切相關(guān)。 ②應(yīng)用FASGAI描述符對30個delta阿片六肽進行序列結(jié)構(gòu)表征，結(jié)合逐步回歸(SMR)篩選變量，建立MLR模型和偏最小二乘(PLS)模型。經(jīng)對比，8變量MLR建模結(jié)果較優(yōu)。最優(yōu)模型的擬合、交互驗證的復(fù)相關(guān)系數(shù)分別為0.891和0.756，基于所建模型，設(shè)計30條活性較高的delta阿片肽。通過分子對接，研究阿片肽與delta阿片受體可能作用模式。本章從2D的角度進一步證明N末端第三個氨基酸對活性具有重要的影響，5號位和6號位次之。同時運用2D方法設(shè)計的分子與運用3D方法設(shè)計的分子對受體上作用位點的選擇相似。 ③應(yīng)用FASGAI描述符對277條六肽進行序列結(jié)構(gòu)表征，結(jié)合徑向基核支持向量機(RBF-SVM)建立淀粉樣肽的預(yù)測模型，得留五法交互驗證的正確率為74.37%，受試者操作特征曲線下面積(AUC)為0.759。對淀粉樣肽構(gòu)效關(guān)系分析，氨基酸的疏水性質(zhì)與靜電性質(zhì)對蛋白質(zhì)聚集具有關(guān)鍵作用。采用6-殘基窗口掃描Aβ42和hIAPP37兩種蛋白中的六肽并預(yù)測其可聚集性，對比發(fā)現(xiàn)，模型識別出可聚集六肽片段與實驗報道結(jié)果具有較好一致性�；诖四Ｐ停O(shè)計558條可能聚集的六肽。結(jié)合模型預(yù)測的Aβ42上的GGVVIA序列和先前設(shè)計的8條六肽，運用分子動力學(xué)和量子化學(xué)方法分析，并輔以圓二色譜(CD)實驗驗證。結(jié)果顯示以一種作用方式的能量占優(yōu)，適度大小的側(cè)鏈，均勻的能量分布有利于多肽聚集。所設(shè)計多肽AEFRHD可能具有較好聚集能力。
[Abstract]:As a key material for maintaining the normal functioning of the living organism , the polypeptide is more and more concerned with the human being , especially its medicinal value , and in recent years , its application in the material has become more and more prominent . However , the structure and function of certain polypeptide have some defects , so the optimization and modification of its structure can help to design a more reasonable polypeptide compound . In this paper , the quantitative structure - effect relationship and mechanism of two kinds of peptides were studied by means of two - dimensional quantitative structure - effect relationship ( 2D - activity relationship ) and three - dimensional quantitative structure - effect relationship ( 3D - quantitative analysis ) . The structure of the polypeptide was optimized by means of multi - linear regression ( MLR ) , support vector machine ( SVM ) , Topomer CoAs and Topomer Search and molecular docking method . The structure of the polypeptide was optimized . The design molecule was evaluated by molecular dynamics and quantum chemistry . The results obtained were as follows : The results showed that the activity of the third amino acid of delta opioid peptide was higher than that of template molecule . The results showed that the third amino acid of delta opioid peptide was higher than that of template molecule . The results showed that the third amino acid of delta opioid N was important to the activity . The results showed that the amino acid of the delta opioid N was highly active in the selection and activity of ligand . The results of single - point energy showed that His278 might be closely related to the activity of delta opioid peptide . ( 2 ) Using the FASGAI descriptor to characterize the sequence structure of 30 delta opioid hexpeptides , combined stepwise regression ( SMR ) screening variables , an MLR model and a partial least squares ( PLS ) model were established . Based on this model , the six peptides of A尾42 and hIAPP37 were analyzed by molecular dynamics and quantum chemistry method .

【學(xué)位授予單位】：重慶大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914.5;R91

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