發(fā)布時間：2018-03-29 17:36

  本文選題：臨界性　切入點：蛋白質(zhì)　出處：《南京大學(xué)》2016年博士論文

【摘要】：在復(fù)雜系統(tǒng)中常常具有一些從系統(tǒng)整體層次展現(xiàn)出來的、無法還原為系統(tǒng)較低層次上簡單因素的特征或規(guī)律,這些從系統(tǒng)整體層次表現(xiàn)出來的現(xiàn)象即為復(fù)雜系統(tǒng)的涌現(xiàn)行為.近年來,越來越多的實驗和觀測都表明,生命系統(tǒng)作為一種典型的非平衡系統(tǒng),常常通過自組織臨界工作在某種與相變的“臨界點”類似的狀態(tài)上.復(fù)雜系統(tǒng)在臨界點附近可能涌現(xiàn)出許多重要的物理行為,尤其對生命系統(tǒng)而言,在臨界點附近通�？梢暂^好地保持“穩(wěn)定性”和“適應(yīng)性”之間的平衡.例如在各種生物的集體行為和各類復(fù)雜的生物網(wǎng)絡(luò)中,系統(tǒng)既需要保持穩(wěn)定的組織性,也需要對環(huán)境中的微小變化保持敏感性,而處在臨界態(tài)的系統(tǒng)正好可以滿足這兩方面的條件：構(gòu)成系統(tǒng)的個體之間僅僅存在短程的相互作用,就可以使得整個系統(tǒng)(例如動物群體的集體行為和神經(jīng)動力學(xué))卻表現(xiàn)出長程的關(guān)聯(lián).蛋白質(zhì)是生命活動的承載者,在生物體內(nèi)發(fā)揮多種多樣的功能.對于蛋白質(zhì)分子而言,它們既具有穩(wěn)定的天然態(tài)結(jié)構(gòu),又在行使其功能時足夠靈活和敏感,在發(fā)生構(gòu)象變化時可以保持一定的靈活性,使得分子可以發(fā)生大尺度的構(gòu)象變化.這兩種基本要求看起來相互矛盾,而當(dāng)體系處在臨界點附近時,其穩(wěn)定性和靈活性有可能共存.我們對蛋白質(zhì)的天然態(tài)結(jié)構(gòu)進(jìn)行了研究.我們通過對核磁共振方法測定的蛋白質(zhì)結(jié)構(gòu)出發(fā),從這些數(shù)據(jù)中提取出蛋白質(zhì)在天然態(tài)結(jié)構(gòu)附近的漲落特征,通過計算這些漲落中的關(guān)聯(lián),直接證明了蛋白質(zhì)天然態(tài)漲落的臨界特征.在蛋白質(zhì)的天然態(tài)漲落中,漲落的關(guān)聯(lián)長度與蛋白質(zhì)分子的尺寸成正比,而這些天然態(tài)結(jié)構(gòu)中存在著大量的冪律.我們還通過統(tǒng)計說明這些臨界的特征對于不同結(jié)構(gòu)、不同功能的蛋白質(zhì)分子是普遍存在的.蛋白質(zhì)天然態(tài)附近的臨界動力學(xué)與蛋白質(zhì)的進(jìn)化有著緊密的聯(lián)系：具有臨界特征的蛋白質(zhì)在進(jìn)化的過程中具有適應(yīng)度的優(yōu)勢,它們既具有進(jìn)化上和結(jié)構(gòu)上的穩(wěn)定性,又具有可進(jìn)化性以及發(fā)揮生物學(xué)功能的能力.為了進(jìn)一步分析這種臨界性的起源,基于蛋白質(zhì)的序列進(jìn)化和天然態(tài)結(jié)構(gòu)的信息,采用網(wǎng)絡(luò)分析的方法,深入研究了共進(jìn)化直接耦合網(wǎng)絡(luò)和殘基接觸網(wǎng)絡(luò)(彈性網(wǎng)絡(luò)模型)的性質(zhì).目前的研究表明這兩種不同類型的網(wǎng)絡(luò)本身是高度相似的.我們證明,對這些網(wǎng)絡(luò)而言,在拓?fù)淇臻g中,蛋白質(zhì)分子的無標(biāo)度漲落特征仍然是存在的.此外,通過以無序堆積的粒子形成的網(wǎng)絡(luò)結(jié)構(gòu)作為對照,我們證明了蛋白質(zhì)的這種臨界性與其天然態(tài)結(jié)構(gòu)是相關(guān)的.我們還發(fā)現(xiàn)：氨基酸殘基的度度關(guān)聯(lián)表明這一網(wǎng)絡(luò)具有無標(biāo)度網(wǎng)絡(luò)的特征,并且殘基接觸網(wǎng)絡(luò)表現(xiàn)出模塊化和層級化的特征,而跟隨機(jī)堆積相比,氨基酸殘基的堆積表現(xiàn)出高聚集系數(shù)和非小世界的特點,反映到分子的振動模式上,則對應(yīng)于相比隨機(jī)堆積更低的最低頻模式,這些低頻模式的頻率與蛋白質(zhì)的形狀和表面積等是直接相關(guān)的.我們的這一分析揭示了蛋白質(zhì)天然態(tài)結(jié)構(gòu)臨界性的序列進(jìn)化和結(jié)構(gòu)基礎(chǔ).蛋白質(zhì)天然態(tài)漲落表現(xiàn)出明顯的臨界特征,因而分子內(nèi)的關(guān)聯(lián)長度會隨著分子尺寸的增加而增加,但分子內(nèi)的相互作用力程并不會發(fā)生改變.為了深入研究這一現(xiàn)象的原因,我們對蛋白質(zhì)分子內(nèi)的這種長程關(guān)聯(lián)進(jìn)行了更深入的統(tǒng)計分析.我們利用了關(guān)聯(lián)矩陣和相互作用矩陣的互逆關(guān)系,設(shè)計了一種自洽的方法,對殘基間距離依賴的相互作用進(jìn)行了推斷,這一方法利用了殘基本身相互作用的一些信息,計算的效率比極大熵方法等更高.我們的這一方法可以得到殘基間相互作用的許多重要特征,且其推斷的相互作用強度與統(tǒng)計勢也是相關(guān)的.我們關(guān)于蛋白質(zhì)動力學(xué)中若干涌現(xiàn)特征的研究揭示了蛋白質(zhì)結(jié)構(gòu)和功能之間的基本關(guān)系.這一結(jié)果表明：蛋白質(zhì)的天然態(tài)結(jié)構(gòu)不只要求其處在能量面的最小值處,并且,蛋白質(zhì)的天然態(tài)結(jié)構(gòu)還保持著其動態(tài)的柔性.在自然選擇中被選擇的這些蛋白質(zhì)的天然態(tài)結(jié)構(gòu)可以保證氨基酸殘基間長程關(guān)聯(lián)的出現(xiàn),這對于蛋白質(zhì)發(fā)生構(gòu)象變化和保持穩(wěn)定的天然態(tài)結(jié)構(gòu)都是很重要的.我們的研究結(jié)果還對蛋白質(zhì)設(shè)計、蛋白質(zhì)的聚集以及蛋白質(zhì)的折疊和進(jìn)化等諸多問題具有重要的參考價值.
[Abstract]:In a complex system often has some from the system level to show out, can not be reduced to a relatively low level of simple system features or rules of these factors, from the system level performance of the whole phenomenon is the emergence of behavior of complex systems. In recent years, more and more experiments and observations have shown that as a life system non equilibrium system of typical, often through the self organized critical work in a phase transition and "critical point" of similar state. The complex system may be the emergence of many important physical behavior near the critical point, especially on the life of the system, in the vicinity of the critical point is usually between good stability and adaptability "the balance. For example in a variety of biological collective behavior and all kinds of complex biological networks, the system needs to maintain the stability of the organization, but also the need for small change in the environment Keep sensitive in the critical state of the system can satisfy the two conditions: only the existence of interaction between the short-range system which consists of the individual, can make the whole system (such as animal collective behavior and neural dynamics) has shown long-range correlation. The protein is the bearer of life activities, play a variety of functions in organism. For protein molecules, they have not only the natural state of stable structure, and in the exercise of its function is sufficiently flexible and sensitive, can maintain a certain flexibility in the conformational change, the molecular conformational changes can occur in large scale. The two basic requirements seem contradictory, but when the system is near the critical point, its stability and flexibility. We may coexist on the protein native structure is studied. We based on NMR Protein structure determination method of resonance, extract the fluctuation characteristics of protein in the vicinity of the natural state of the structure from the data, by calculating the correlation of these fluctuations in the direct proof of the critical characteristics of the natural state of protein fluctuations. In the natural state of fluctuation of protein, fluctuation correlation length and protein size is proportional to the there are a large number of these natural power-law structure. We also illustrate these critical features through statistics for different structures, different functions of the protein molecule is universal. The natural state of critical dynamics near the protein and protein evolution are closely linked with the critical feature protein with fitness advantage in evolution in the process, they both stability and structure evolution, and evolution also has the ability to play the biological functions. Further analysis of the origins of this critical, protein sequence evolution and natural state structure based on information, using the method of network analysis, in-depth study of the direct coupling network co evolution and residue contact network (elastic network model) properties. The present study shows that these two different types of network itself is highly similar. We show that, for these networks, in the topology space, protein scale-free fluctuation characteristics still exists. In addition, the network structure formed by the disordered accumulation of particles as the control, we permit this critical and natural state is related to protein structure and clear. We also found that the degree of association amino acid residues show that this network has the characteristics of scale-free network, and the residue contact network shows characteristics of modular and hierarchical, with random accumulation than amino acid The accumulation of residues showed high accumulation coefficient and non small world, to reflect the molecular vibrational modes, corresponding to the low frequency mode compared to random packing of lower frequency and low frequency mode, the protein shape and surface area are directly related. This analysis we revealed the sequence evolution and structure based protein native structure of protein. The critical natural state fluctuation showed critical characteristics, and the correlation length in the molecule will increase with the increase of molecular size, but the interaction range in the molecule and does not change. In order to study the reasons of this phenomenon, we on protein in the the long-range correlation has been statistically analyzed deeply. We use the inverse relationship between the incidence matrix and the interaction matrix, design a self consistent method, the distance between the residues in The interaction of Lai was deduced, this method uses some information interaction residues, the calculation efficiency is higher than the maximum entropy method. This method we can get many important features of the interaction between residues, interaction strength and potential and the statistical inference is also relevant. Us about some emerging features of protein dynamics research reveals the basic relationship between protein structure and function. The results show that the natural state of the protein structure not only requires its energy in the minimum value, and the natural state of structural protein keeps its dynamic flexibility. These proteins are natural state structure selection in natural selection can guarantee the emergence of long-range correlations among amino acid residues, the protein conformational change and maintain the stability of the native state structure is very important Our results also have important reference value for protein design, protein aggregation, protein folding and evolution, and many other problems.

【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：Q615
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本文編號：1682140