【摘要】：G蛋白偶聯(lián)受體(GPCR)的結(jié)構(gòu)特征及其在信號傳導(dǎo)中的重要作用，決定了其可以作為重要的藥物靶標(biāo)， GPCR在制藥領(lǐng)域中占有極其重要的地位。由于生化實驗方法很難得到其三維結(jié)構(gòu)，所以通過計算機(jī)方法預(yù)測其結(jié)構(gòu)具有重大意義。本文在GPCR結(jié)構(gòu)預(yù)測中引入并行技術(shù)，研究GPCR骨架和側(cè)鏈結(jié)構(gòu)預(yù)測問題。 考慮到GPCR跨膜螺旋區(qū)域（TMH）同源性較高，而連接TMH的loop區(qū)域同源性很低，本文基于當(dāng)前主流的GPCR蛋白質(zhì)結(jié)構(gòu)預(yù)測方法提出了一種并行化的GPCR骨架結(jié)構(gòu)預(yù)測方法pGPCR。該方法在構(gòu)建TMH區(qū)域時采用基于模板的方法，在構(gòu)建loop時采用從頭預(yù)測的方法。將并行技術(shù)引入到loop預(yù)測中，在loop并行折疊過程中考慮到loop之間的相互影響，使得整個預(yù)測過程更加符合自然的折疊過程。用pGPCR對最新的權(quán)威測試中兩個案例的三維結(jié)構(gòu)進(jìn)行了預(yù)測，從整體結(jié)果集的質(zhì)量上來看，本文方法不僅在TMH部分能夠取得好的結(jié)果，，而且結(jié)果集中ECL2部分質(zhì)量也較高。實驗結(jié)果還表明，對于具有β折疊這種loop之間存在強(qiáng)烈相互影響的loop區(qū)域，本文預(yù)測的結(jié)果也更加接近天然結(jié)構(gòu)。 在GPCR側(cè)鏈預(yù)測研究方面，本文首先改進(jìn)了GPCR側(cè)鏈搜索空間生成方法，考慮了側(cè)鏈之間的相互影響，提出了一種基于四層推理模型的旋轉(zhuǎn)異構(gòu)體庫構(gòu)造方法，并對3種GPCR蛋白質(zhì)進(jìn)行了側(cè)鏈預(yù)測實驗，驗證了本文生成的旋轉(zhuǎn)異構(gòu)體庫質(zhì)量接近于流行的方法。本文又采用了新的側(cè)鏈預(yù)測并行搜索方法，在共享信息素矩陣的基礎(chǔ)上，并行化多個蟻群，并多樣化各個蟻群的能量函數(shù)和參數(shù)。然后用該方法對pGPCR生成的最好的5個結(jié)果進(jìn)行了側(cè)鏈預(yù)測，結(jié)果表明本文方法具有一定的競爭力。
[Abstract]:The structural characteristics of G-protein-coupled receptor (GPCR) and its important role in signal transduction determine that it can be used as an important drug target, and GPCR plays an extremely important role in pharmaceutical field. Because it is difficult to obtain the three-dimensional structure by biochemical experiment method, it is of great significance to predict its structure by computer method. In this paper, parallel technique is introduced into GPCR structure prediction to study the prediction of GPCR skeleton and side chain structure. Considering the high homology of (TMH) in transmembrane helical region of GPCR and the low homology of loop region connected with TMH, this paper proposes a parallel GPCR skeleton structure prediction method pGPCR. based on the current mainstream GPCR protein structure prediction method. In this method, template based method is used to construct TMH region, and ab initio prediction method is used to construct loop. The parallel technique is introduced into loop prediction, and the interaction between loop is considered in the process of loop parallel folding, which makes the whole prediction process more consistent with the natural folding process. PGPCR is used to predict the 3D structure of the two cases in the latest authoritative test. From the quality of the whole result set, this method can not only obtain good results in the TMH part, but also the higher quality of the ECL2 part in the result set. The experimental results also show that the predicted results of this paper are closer to the natural structure for the loop region with strong interaction between loop and 尾 -fold. In the aspect of GPCR side chain prediction, this paper first improves the GPCR side chain search space generation method, considers the interaction between the side chains, and proposes a new method to construct the rotating isomer library based on the four-layer reasoning model. The side chain prediction experiments of three kinds of GPCR proteins were carried out, and the results showed that the quality of the rotating isomer pool was close to that of the popular method. Based on the shared pheromone matrix, a new side-chain predictive parallel search method is proposed to parallelize multiple ant colonies and diversify the energy functions and parameters of each ant colony. Then the best five results generated by pGPCR are predicted by this method, and the results show that the proposed method is competitive to some extent.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R341

【參考文獻(xiàn)】

相關(guān)期刊論文 前2條

1 繆大俊;呂強(qiáng);黃旭;;一種基于四層推理模型的旋轉(zhuǎn)異構(gòu)體庫構(gòu)造方法[J];蘇州大學(xué)學(xué)報(自然科學(xué)版);2011年04期

2 繆大俊;呂強(qiáng);吳宏杰;陳沙沙;;一種并行化的GPCR結(jié)構(gòu)預(yù)測方法[J];蘇州大學(xué)學(xué)報(自然科學(xué)版);2012年03期

本文編號：2409559