几种转运蛋白的功能理论研究
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摘要
转运蛋白质可以协助具有生物活性的分子穿过特定环境介质（如细胞膜或水溶液），在药物的投送，释放，吸收，及神经信号传导过程中起到关键作用。因此研究具有生物活性的小分子与其载体蛋白结合后的转运和释放问题对于生命科学基础研究和应用都具有十分重要的现实意义，是当前生命科学和药剂学等领域的研究热点。分子的转运与释放问题研究涉及许多生物化学与生物物理的重要基础问题：比如分子识别选择性与专一性问题；配体诱导受体构象变化与构象选择机理；分子结合和释放控制因素等。因此，研究分子的转运与释放不仅对于理解生物体调控机制提供支持，更为重要的是，可为开发高效，安全的药物投送系统提供必要的理论基础。
近年来，随着信息技术的快速发展，分子模拟方法已经成为研究生物体系作用机制及其动态过程的重要手段之一，为从分子、亚基甚至原子层次上了解生命现象及揭示其本质规律提供了一种有效的手段，并为相应的实验工作提供有力的理论支持。在当前论文工作中，我们主要通过分子模拟方法系统研究了小分子通过其对应的转运蛋白的结合，转运，释放问题。
本论文主要工作内容包括以下三部分：
1．分子模拟研究来自南方居所蚊虫气味结合蛋白配体释放机理
信息素结合蛋白可以转运具有疏水性质的信息素分子通过水介质到达其相应的蛋白受体。致乏库蚊子的气味结合蛋白作为一种结合产卵信息素((5R,6S)-6-乙酰氧基-5-十六内酯:MOP)其在传感产卵信号中起到关键作用。然而，目前产卵信息素（MOP）从气味结合蛋白的释放机理还不清楚。当前这个研究工作中，我们利用常规分子动力学模拟方法、主成分分析和本质动力学采样方法揭示了产卵信息素(MOP)从气味结合蛋白的释放路径和释放过程。进一步分析表明：产卵信息素分子(MOP)的内在的柔性、气味结合蛋白对产卵信息素分子(MOP)相互作用的分布和气味结合蛋白的局部构象变化是控制产卵信息素分子释放的关键因素。
2．分子模拟研究新制癌菌素的发色团分子的释放机理
新制癌菌素作为一种抗肿瘤的发色团分子的携带蛋白在临床和医药研发有很多重要的应用，比如它已经作为一种药物投送系统在临床治疗中使用。目前发色团分子从新制癌菌素的释放过程仍然是不清楚的，在当前这个研究工作中，我们利用常规分子动力学模拟方法和本质动力学采样方法揭示了发色团分子从结合蛋白的释放路径和释放过程，模拟结果与Chin等人基于实验结果提出的发色团分子释放模型是一致的[J Biol Chem281:16025,2006]。进一步分析结果表明：携带蛋白的的loop区域（loop99-104）的构象变化和其第78号氨基酸（Phe78）的侧链运动是控制发色团分子释放的关键因素；而loop99-104是释放过程发生的重要前提条件。
3．多尺度分子模拟研究来自于无类囊体蓝藻的五聚体门控离子通道门控机理
五聚体门控离子通道是一个重要膜蛋白家族，在生理学过程中起到重要作用。我们以来自无类囊体蓝藻（Gloebacter violaceus:GLIC）的五聚体门控离子通道X-ray结构为模型，进行总共1.05μs的粗粒化分子模拟，并结合原子级分子模拟方法，观察到其离子通道的闭合和相应的四级结构扭转。我们发现其位于跨膜区组成通道的M2螺旋通过倾斜-旋转（指向通道中心）的协调运动来完成通道闭合。进一步分析并结合前人的实验结果，我们提出了描述该离子通道门控过程的“连锁反应”机理：由单独亚基的M2螺旋前部构象变化引发，使该亚基发生整体的构象变化，并且将这种变化传递到了邻近的亚基，进而带动整个通道的构象变化，最终完成通道的闭合。
Transporter proteins can facilitate bioactive small molecules through specificenvironmental medias (such as the cell membrane or aqueous solution), and play akey role in the delivery, release, absorption of the drug and nerve signaling processes.Studying the transport and release of bioactive small molecule with its carrier proteinfor basic research and applications of bioscience is very important, and is also thecurrent hot topic in the life sciences and pharmacy. The process of molecular transportand release involving many basic questions of biochemistry and biophysics: such asselective and specificity of molecular recognition; ligand-induced conformationalchanges or conformational selection mechanism; drug molecule controllable releasingfactors. Therefore, carrying out researches for molecular transport and release notonly make me understand well for biological system regulatory mechanism, it is moreimportant that provide the crucial theoretical basis for the development of efficient,safe drugs delivery system.
In recent years, with the rapid development of information technology, molecularsimulation has become an important means for studying the mechanism of biologicalsystems and their dynamic processes and can give us much information forunderstanding and revealing the essential rules of the phenomenon of life frommolecular subunits or even atomic-level, and also can provide strong theoreticalsupport for the experimental works. In this thesis work, I have studied on themechanism transporting and releasing of molecules assisted by transporter proteinusing molecular simulation methods.
The main contents include the following three parts:
1. Molecular simulations study of Ligand-release mechanism in an odorant-bindingprotein from the southern house mosquito
Pheromone-binding proteins (PBP) transport hydrophobic pheromones throughthe aqueous medium to their receptors. The odorant binding protein (OBP) of Culexquinquefasciatus (CquiOBP1), which binds to an oviposition pheromone(5R,6S)-6-acetoxy-5-hexadecanolide(MOP), plays a key role in sensing ovipositioncues. However, so far the mechanism of MOP-release from the protein is unclear. Therefore, in this contribution the process and pathway of the MOP-release fromCquiOBP1are determined by conventional MD, essential dynamics and essentialdynamics sampling. The detailed analysis of the release process suggests the intrinsicflexibility of MOP, the distribution of contacts with MOP and local conformationalchanges of CquiOBP1are crucial.
2. Molecular simulations of neocarzinostatin chromophore release mechanism
Neocarzinostatin (NCS) is an antitumor chromophore carrier protein with manyapplications in clinical use such as drug delivery system; however, so far itschromophore-releasing mechanism remains unclear. In this contribution the processand pathway of the chromophore releasing from holoprotein are revealed byconventional molecular dynamics simulations and essential dynamics (ED) samplingmethod. The results are consistent with the model for ligand release proposed by D.HChin et al.(J. Biol. Chem.,2006,281,16025–16033). The further analysis suggeststhat the conformational changes of loop99–104and motions of side-chain of residuePhe78are important factors for chromophore release; the opening state of loop99-104is a precondition for the release of ligand.
3. Multi-scale Molecular Simulations Study on the Gating Mechanism in a PentamericLigand-gated Ion Channel from Gloebacter Violaceus
Pentameric ligand-gated ion channels belong to an important family ofmembrane proteins and play key roles in physiological processes. Based on the X-raystructure of prokaryotic pentameric ligand-gated ion channels from Gloebacterviolaceus (GLIC), we performed a total of1.05μs coarse-grained molecularsimulations, combining with atomic-level molecular simulation, and observed thepore closure and corresponding quaternary twist. We found that the pore closure by aconcerted motion of rotating-tilting (toward the pore) of helices M2. Combining withprevious experimental results, a model of describing the conformational transition forchannel gating process is derived from our simulations: the top of the M2helix occurslarge conformational fluctuations, followed by a global conformational changes of thewhole subunit; this process passes from one subunit to the neighbor one, finally,leading to the entire channel conformational changes, such as a “chain-reaction”.
近年来，随着信息技术的快速发展，分子模拟方法已经成为研究生物体系作用机制及其动态过程的重要手段之一，为从分子、亚基甚至原子层次上了解生命现象及揭示其本质规律提供了一种有效的手段，并为相应的实验工作提供有力的理论支持。在当前论文工作中，我们主要通过分子模拟方法系统研究了小分子通过其对应的转运蛋白的结合，转运，释放问题。
本论文主要工作内容包括以下三部分：
1．分子模拟研究来自南方居所蚊虫气味结合蛋白配体释放机理
信息素结合蛋白可以转运具有疏水性质的信息素分子通过水介质到达其相应的蛋白受体。致乏库蚊子的气味结合蛋白作为一种结合产卵信息素((5R,6S)-6-乙酰氧基-5-十六内酯:MOP)其在传感产卵信号中起到关键作用。然而，目前产卵信息素（MOP）从气味结合蛋白的释放机理还不清楚。当前这个研究工作中，我们利用常规分子动力学模拟方法、主成分分析和本质动力学采样方法揭示了产卵信息素(MOP)从气味结合蛋白的释放路径和释放过程。进一步分析表明：产卵信息素分子(MOP)的内在的柔性、气味结合蛋白对产卵信息素分子(MOP)相互作用的分布和气味结合蛋白的局部构象变化是控制产卵信息素分子释放的关键因素。
2．分子模拟研究新制癌菌素的发色团分子的释放机理
新制癌菌素作为一种抗肿瘤的发色团分子的携带蛋白在临床和医药研发有很多重要的应用，比如它已经作为一种药物投送系统在临床治疗中使用。目前发色团分子从新制癌菌素的释放过程仍然是不清楚的，在当前这个研究工作中，我们利用常规分子动力学模拟方法和本质动力学采样方法揭示了发色团分子从结合蛋白的释放路径和释放过程，模拟结果与Chin等人基于实验结果提出的发色团分子释放模型是一致的[J Biol Chem281:16025,2006]。进一步分析结果表明：携带蛋白的的loop区域（loop99-104）的构象变化和其第78号氨基酸（Phe78）的侧链运动是控制发色团分子释放的关键因素；而loop99-104是释放过程发生的重要前提条件。
3．多尺度分子模拟研究来自于无类囊体蓝藻的五聚体门控离子通道门控机理
五聚体门控离子通道是一个重要膜蛋白家族，在生理学过程中起到重要作用。我们以来自无类囊体蓝藻（Gloebacter violaceus:GLIC）的五聚体门控离子通道X-ray结构为模型，进行总共1.05μs的粗粒化分子模拟，并结合原子级分子模拟方法，观察到其离子通道的闭合和相应的四级结构扭转。我们发现其位于跨膜区组成通道的M2螺旋通过倾斜-旋转（指向通道中心）的协调运动来完成通道闭合。进一步分析并结合前人的实验结果，我们提出了描述该离子通道门控过程的“连锁反应”机理：由单独亚基的M2螺旋前部构象变化引发，使该亚基发生整体的构象变化，并且将这种变化传递到了邻近的亚基，进而带动整个通道的构象变化，最终完成通道的闭合。
Transporter proteins can facilitate bioactive small molecules through specificenvironmental medias (such as the cell membrane or aqueous solution), and play akey role in the delivery, release, absorption of the drug and nerve signaling processes.Studying the transport and release of bioactive small molecule with its carrier proteinfor basic research and applications of bioscience is very important, and is also thecurrent hot topic in the life sciences and pharmacy. The process of molecular transportand release involving many basic questions of biochemistry and biophysics: such asselective and specificity of molecular recognition; ligand-induced conformationalchanges or conformational selection mechanism; drug molecule controllable releasingfactors. Therefore, carrying out researches for molecular transport and release notonly make me understand well for biological system regulatory mechanism, it is moreimportant that provide the crucial theoretical basis for the development of efficient,safe drugs delivery system.
In recent years, with the rapid development of information technology, molecularsimulation has become an important means for studying the mechanism of biologicalsystems and their dynamic processes and can give us much information forunderstanding and revealing the essential rules of the phenomenon of life frommolecular subunits or even atomic-level, and also can provide strong theoreticalsupport for the experimental works. In this thesis work, I have studied on themechanism transporting and releasing of molecules assisted by transporter proteinusing molecular simulation methods.
The main contents include the following three parts:
1. Molecular simulations study of Ligand-release mechanism in an odorant-bindingprotein from the southern house mosquito
Pheromone-binding proteins (PBP) transport hydrophobic pheromones throughthe aqueous medium to their receptors. The odorant binding protein (OBP) of Culexquinquefasciatus (CquiOBP1), which binds to an oviposition pheromone(5R,6S)-6-acetoxy-5-hexadecanolide(MOP), plays a key role in sensing ovipositioncues. However, so far the mechanism of MOP-release from the protein is unclear. Therefore, in this contribution the process and pathway of the MOP-release fromCquiOBP1are determined by conventional MD, essential dynamics and essentialdynamics sampling. The detailed analysis of the release process suggests the intrinsicflexibility of MOP, the distribution of contacts with MOP and local conformationalchanges of CquiOBP1are crucial.
2. Molecular simulations of neocarzinostatin chromophore release mechanism
Neocarzinostatin (NCS) is an antitumor chromophore carrier protein with manyapplications in clinical use such as drug delivery system; however, so far itschromophore-releasing mechanism remains unclear. In this contribution the processand pathway of the chromophore releasing from holoprotein are revealed byconventional molecular dynamics simulations and essential dynamics (ED) samplingmethod. The results are consistent with the model for ligand release proposed by D.HChin et al.(J. Biol. Chem.,2006,281,16025–16033). The further analysis suggeststhat the conformational changes of loop99–104and motions of side-chain of residuePhe78are important factors for chromophore release; the opening state of loop99-104is a precondition for the release of ligand.
3. Multi-scale Molecular Simulations Study on the Gating Mechanism in a PentamericLigand-gated Ion Channel from Gloebacter Violaceus
Pentameric ligand-gated ion channels belong to an important family ofmembrane proteins and play key roles in physiological processes. Based on the X-raystructure of prokaryotic pentameric ligand-gated ion channels from Gloebacterviolaceus (GLIC), we performed a total of1.05μs coarse-grained molecularsimulations, combining with atomic-level molecular simulation, and observed thepore closure and corresponding quaternary twist. We found that the pore closure by aconcerted motion of rotating-tilting (toward the pore) of helices M2. Combining withprevious experimental results, a model of describing the conformational transition forchannel gating process is derived from our simulations: the top of the M2helix occurslarge conformational fluctuations, followed by a global conformational changes of thewhole subunit; this process passes from one subunit to the neighbor one, finally,leading to the entire channel conformational changes, such as a “chain-reaction”.
引文
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