【摘要】：RNA是生物體中一種非常重要的生物大分子,它結(jié)構(gòu)多樣,功能豐富,在生命的遺傳和進(jìn)化方面扮演著非常重要的角色,比如,遺傳信息的保存,轉(zhuǎn)錄,翻譯,調(diào)控和復(fù)制等等。然而,RNA分子要實(shí)現(xiàn)這些生物功能,必須從單鏈結(jié)構(gòu)折疊成二級(jí)結(jié)構(gòu)或更為復(fù)雜的三級(jí)結(jié)構(gòu),在這些功能結(jié)構(gòu)折疊的過(guò)程中,單個(gè)堿基對(duì)的打開(kāi)與閉合是非常重要而且是必經(jīng)的過(guò)程,并且功能結(jié)構(gòu)的形成往往是動(dòng)力學(xué)控制,并依賴(lài)于堿基對(duì)的打開(kāi)與閉合的速率。所以,深入理解單個(gè)堿基對(duì)的開(kāi)關(guān)特性是進(jìn)一步探索RNA分子更多生物功能的基礎(chǔ)和關(guān)鍵。由于堿基對(duì)在常溫下很難打開(kāi),所以,本文我們采用在融解溫度附近的高溫分子動(dòng)力學(xué)模擬計(jì)算方法,研究了單個(gè)堿基對(duì)的打開(kāi)與閉合的熱力學(xué)性質(zhì)和動(dòng)力學(xué)機(jī)制,以及溶液中離子濃度和不同近鄰堿基對(duì)單個(gè)堿基對(duì)的熱力學(xué)和動(dòng)力學(xué)的影響。主要的研究?jī)?nèi)容如下：(1)單個(gè)堿基對(duì)的熱力學(xué)和動(dòng)力學(xué)當(dāng)離子濃度為0.5M時(shí),根據(jù)模擬溫度分別為390K,400K,410K,420K和430K的模擬軌跡,建立了從動(dòng)力學(xué)模擬軌跡來(lái)表征堿基對(duì)處于打開(kāi)態(tài),閉合態(tài)和過(guò)度態(tài)的方法,得到了末端單個(gè)堿基對(duì)AU的熱力學(xué)參數(shù)及開(kāi)關(guān)動(dòng)力學(xué)。在熱力學(xué)方面,根據(jù)模擬軌跡在平衡狀態(tài)時(shí)打開(kāi)與閉合的平衡幾率分布,得到了打開(kāi)態(tài)與閉合態(tài)之間的焓變和熵變,和實(shí)驗(yàn)上最近鄰模型參數(shù)吻合的非常好。在動(dòng)力學(xué)方面,得到了閉合態(tài),打開(kāi)態(tài)和過(guò)渡態(tài)的平均壽命,以及堿基對(duì)的打開(kāi)速率,閉合速率和轉(zhuǎn)變路徑速率。研究結(jié)果顯示,閉合態(tài)平均壽命是與溫度呈現(xiàn)較強(qiáng)的關(guān)聯(lián)性,而打開(kāi)態(tài)和過(guò)渡態(tài)的平均壽命則與溫度呈現(xiàn)較弱的關(guān)聯(lián)性。另外,閉合態(tài)與打開(kāi)態(tài)之間的轉(zhuǎn)變路徑時(shí)間也與溫度呈現(xiàn)較弱的關(guān)聯(lián)性,并且對(duì)躍遷的能量勢(shì)壘的高度不敏感。通過(guò)分析,研究結(jié)果表明,RNA分子結(jié)構(gòu)中單個(gè)堿基對(duì)從閉合到打開(kāi)的過(guò)程中,克服的自由能勢(shì)壘是堿基對(duì)之間的氫鍵相互作用和與鄰近堿基之間的堆積相互作用所引起的焓的增加,而從打開(kāi)到閉合的過(guò)程中,克服的自由能勢(shì)壘是磷酸骨架扭轉(zhuǎn)角的限制和溶劑粘性等等所引起的熵的減小。這進(jìn)一步說(shuō)明一維自由能勢(shì)能面是可以精確描述堿基對(duì)的打開(kāi)與閉合的動(dòng)力學(xué),并且這個(gè)動(dòng)力學(xué)是布朗運(yùn)動(dòng),擴(kuò)散常數(shù)展現(xiàn)出了超阿列紐斯特性。(2)離子濃度對(duì)單個(gè)堿基對(duì)的熱力學(xué)和動(dòng)力學(xué)的影響在第一研究工作的基礎(chǔ)之上,又分別研究了離子濃度為0.1M和0.05M時(shí)堿基對(duì)AU的熱力學(xué)性質(zhì)和開(kāi)關(guān)動(dòng)力學(xué)機(jī)制,根據(jù)模擬溫度分別為390K,400K,410K和420K的模擬軌跡,得到了堿基對(duì)AU在不同離子濃度下的熱力學(xué)參數(shù)及開(kāi)關(guān)特性,并深入分析了離子濃度對(duì)堿基對(duì)熱力學(xué)和動(dòng)力學(xué)的影響。在熱力學(xué)方面,得到了不同離子濃度下堿基對(duì)在打開(kāi)與閉合之間的焓變和熵變,發(fā)現(xiàn)溶液中離子濃度的改變對(duì)堿基對(duì)的焓變沒(méi)有影響,而熵變隨著離子濃度的減小而增大,和實(shí)驗(yàn)上得出的結(jié)論相一致。在動(dòng)力學(xué)方面,根據(jù)閉合態(tài),打開(kāi)態(tài)和過(guò)渡態(tài)的平均壽命,發(fā)現(xiàn)閉合態(tài)和過(guò)度態(tài)的平均壽命不隨離子濃度的變化而變化,而打開(kāi)態(tài)的平均壽命隨著離子濃度的減小而增大,與實(shí)驗(yàn)上觀測(cè)的結(jié)果相一致。研究結(jié)果表明,在打開(kāi)過(guò)程中,由于堿基對(duì)克服的焓變是一樣的,所以,打開(kāi)速率不隨離子濃度的變化而變化；而在閉合過(guò)程中,由于描述一維自由能勢(shì)能面的粗糙程度受離子濃度的影響,當(dāng)離子濃度越小時(shí),勢(shì)能面越粗糙,存在的構(gòu)象陷阱態(tài)越多,所以,閉合速率隨著離子濃度的減小而變慢,和實(shí)驗(yàn)上的結(jié)論相一致。(3)近鄰堿基對(duì)單個(gè)堿基對(duì)的熱力學(xué)和動(dòng)力學(xué)的影響當(dāng)溶液中的離子濃度均為0.5M時(shí),研究了末端單個(gè)堿基對(duì)GC(5'-GG…3'-CC…)和CG(5'-CA…3'-GU…)在不同近鄰堿基下的熱力學(xué)和動(dòng)力學(xué)。研究結(jié)果表明,最近鄰堿基不僅影響熱力學(xué)參數(shù),即堿基對(duì)開(kāi)關(guān)時(shí)的焓變和熵變,而且在動(dòng)力學(xué)方面影響堿基對(duì)在各個(gè)構(gòu)象態(tài)的平均壽命和它們之間轉(zhuǎn)換速率。另外,不同的最近鄰堿基影響勢(shì)能面的粗糙程度,與實(shí)驗(yàn)上觀測(cè)的結(jié)果相一致。
[Abstract]:RNA is a very important biological macromolecule in the organism, its structure is diverse, the function is rich, plays a very important role in the genetics and evolution of life, such as the preservation, transcription, translation, regulation and replication of the genetic information, etc. However, in order to achieve these biological functions, the RNA molecule must be folded from a single-stranded structure into a secondary structure or a more complex tertiary structure, in which the opening and closing of a single base pair is very important and a required process in the course of the folding of these functional structures, And the formation of functional structures is often dynamic control and depends on the rate of opening and closing of base pairs. Therefore, in-depth understanding of the switching characteristics of a single base pair is the basis and the key to further explore the more biological function of the RNA molecule. Since the base pair is very difficult to open at normal temperature, we use the high-temperature molecular dynamics simulation method near the melting temperature to study the thermodynamic and dynamic mechanism of the opening and closing of a single base pair. And the effect of the ionic concentration in the solution and the thermodynamics and kinetics of a single base pair of different neighbor base pairs. The main contents of the study are as follows: (1) The thermodynamics and kinetics of a single base pair, when the ion concentration is 0.5M, establishes a simulation track of 390K, 400K, 410K, 420K and 430K, respectively, according to the simulated temperature, and establishes a dynamic simulation track to characterize the base pair in an open state, The thermodynamic parameters and the switching dynamics of the single base pair AU are obtained by the method of closed state and over-state. In the thermodynamic aspect, the equilibrium probability distribution of the open and closed states is obtained according to the simulation track in the equilibrium state, and the phase change and the entropy change between the open state and the closed state are obtained, and the parameters of the nearest neighbor model in the experiment are in good agreement with each other. In the kinetic aspect, the average life of the closed state, the open state and the transition state, and the opening rate, the closing rate and the transition path rate of the base pair are obtained. The results show that the average life of the closed state is strongly related to the temperature, and the average life of the open state and the transition state exhibits a weak correlation with the temperature. In addition, the transition path time between the closed state and the open state also exhibits a weak correlation with the temperature and is not sensitive to the height of the energy barrier of the transition. Through the analysis, the results show that the free energy barrier against which the single base pair in the RNA molecular structure is closed to the opening is an increase in the hydrogen bond interaction between the base pairs and the interaction of the accumulation of the adjacent bases, In the process of opening to closing, the free energy barrier to be overcome is the reduction of the entropy caused by the restriction of the twist angle of the phosphoric acid skeleton and the viscosity of the solvent, and the like. This further shows that the one-dimensional free energy potential surface can accurately describe the dynamics of the opening and closing of base pairs, and the kinetics is the Brownian motion, and the diffusion constant exhibits the super-Arrhenius character. (2) The effect of the ion concentration on the thermodynamics and kinetics of a single base pair is based on the first study, and the thermodynamic properties and the switching dynamics of the base pair AU when the ion concentration is 0.1M and 0.05M are respectively studied, and the simulation temperature is 390K and 400K, respectively. The thermodynamic parameters and switching characteristics of base pair AU at different ion concentrations are obtained, and the effect of ion concentration on the thermodynamics and dynamics of base pair is analyzed. In the thermodynamic aspect, the evolution and entropy change of base pair under different ion concentration on the opening and closing are obtained, and the change of the ion concentration in the solution has no effect on the change of the base pair, and the entropy change is increased with the decrease of the ion concentration, and the result is consistent with the conclusion. In the dynamic aspect, the average life of the closed state and the transition state is found to not change with the change of the ion concentration according to the average life of the closed state, the open state and the transition state, and the average life of the open state increases with the decrease of the ion concentration, and is consistent with the results observed in the experiment. The results show that, during the opening process, the opening rate does not change with the change of the ion concentration, and the degree of roughness of the one-dimensional free energy potential surface is affected by the ion concentration during the closing process. The more the ion concentration is, the more rough the potential energy surface, the more the formation trap state, so the closing rate becomes slower with the decrease of the ion concentration, and is in line with the experimental conclusion. (3) The effect of the thermodynamics and kinetics of the single base pair of the nearest neighbor base pair is that when the concentration of the ions in the solution is 0.5M, the single base pair GC (5 '-GG.) at the end is studied. 3 '-CC... ) And CG (5 '-CA... 3 '-GU... ) Thermodynamics and kinetics at different neighbor bases. The results show that the nearest base not only affects the thermodynamic parameters, that is, the evolution and entropy of the base pair switches, but also the average life of the base pairs in the various conformations and the conversion rate of the base pairs in the dynamics. In addition, the different nearest neighbor bases affect the degree of roughness of the potential energy surface, which is consistent with the results observed in the experiment.
【學(xué)位授予單位】：武漢大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：Q615

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