分子动力学模拟在生物大分子体系中的应用
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摘要
近年来，随着计算机水平的不断提高，分子动力学模拟已发展成为生物、化学、物理、材料等领域的一种重要科研手段。应用分子动力学模拟，一方面可以得到体系随时间演变的动态信息，另一方面，也可以得到体系的热力学相关信息。这些信息都是传统实验很难获取的。生命科学目前的发展已经深入到原子水平，分子动力学依靠其在微观水平上精确的控制性以及操作性，在研究蛋白质折叠/去折叠、分子识别、离子运输、酶催化反应机理中也发挥着越来越重要的作用。本文利用分子动力学模拟方法，对几类具有重要生理意义的生物大分子体系进行了系统而详细的研究，主要内容包括以下四个部分：
1.解旋酶Mss116p对双链RNA的识别机制
DEAD-box蛋白质家族是最大的RNA解旋酶家族，与几乎所有涉及到RNA的领域都密切相关。但是，该类蛋白质识别并结合RNA的具体机制尚不明确。在本文中，我们利用分子动力学模拟与MM-GBSA方法，对DEAD-box的模板蛋白Mss116p与双链RNA之间的相互作用进行了深入研究。结合自由能分析的结果表明：双链RNA的两条链与Mss116p的结合活性是不相等的。其中的一条链提供了主要的结合活性，而另一条链与蛋白质几乎没有任何结合活性。同时，在Mss116p与双链RNA的结合过程中，非极性相互作用提供了主要的结合驱动力。虽然极性相互作用对于结合的贡献很小，但它在稳定蛋白质-RNA相互作用时也有着重要作用。与野生型的Mss116p相比，两种突变体，Q412A与D441A与dsRNA的结合自由能有明显的降低，其主要原因是极性相互作用的减少。三个重要的氨基酸残基Lys409,Arg415以及Arg438在突变体中都丧失了结合活性。总的来说，上述结论对实验进行了很好的补充，有助于人们更全面的理解Mss116p的解旋机理。同时，本文中方法的应用也可以推广到DEAD-box家族的其它蛋白质上，用以研究它们的识别机制。
2.马尔堡病毒蛋白VP35对双链RNA的识别机制
线状病毒经常会造成非常严重的传染病，而人们至今依然没有找到有效的药物。所有的线状病毒都可以编码一种叫VP35的蛋白，这种蛋白可以隐藏病毒的遗传物质双链RNA，以此逃脱人体的免疫系统。因此，VP35与双链RNA的接触面将是一个较为可信抗病毒药物设计的靶点。为了研究VP35与双链RNA的识别机制，我们采取了分子动力学模拟与MM-GBSA方法去研究VP35与双链RNA的复合物，并同时研究了几个突变体复合物。能量分析的结果表明非极性相互作用提供了结合的主要驱动力。虽然分子间静电力在VP35与双链RNA的结合中起了非常重要的作用，但整体的极性相互作用却是不利于两者的结合，这也导致了整体结合活性偏低。与野生型VP35相比，三个突变体F228A,R271A与K298A与双链RNA的结合能力有明显的降低。同时，分析结果也表明如果一条RNA链与VP35失去了结合活性，那么整个双链RNA都将与VP35失去结合活性。同时我们还确定了结合过程中最重要的三个残基，Arg271,Arg294以及Lys298，这三个残基在突变体中都失去了结合活性。我们对VP35与双链RNA结合机制的研究成果将有助于开发新的抗病毒药物。
3.维生素H合成过程中BioH的底物特异性研究
众所周知，庚二酰甲酯-ACP复合物是维生素H的前驱化合物，也是其合成过程中的酶BioH的生理底物。而壬二酰甲酯与ACP的复合物也可以被BioH所催化，但是其水解速率非常低。迄今为止，人们对于BioH的底物特异性，以及将庚二酰甲酯的C7链延长到C9之后，水解速率降低的原因还不清楚。为此，我们利用分子动力学模拟与结合自由能计算，研究了碳链伸长对BioH底物结合造成的影响。我们的结果表明底物特异性是由BioH与ACP共同决定的。增加的两个碳的碳链将不会与BioH的疏水空腔产生位阻，而是会造成ACP与BioH接触面上结构的变化。从另一方面说，壬二酰底物过低的水解速率也与BioH及ACP之间结合能力的减弱有关，主要是体现在接触面上两个主要的盐桥、氢键网络的破坏。本文的研究为BioH与庚二酰甲酯-ACP复合物的结构与功能提供了重要的数据，为全面的理解BioH的催化机理奠定了理论基础。
4.突变及低pH环境对transthyretin二聚体稳定性及去折叠机制的影响
Transthyretin的解离与聚集可以引发数种淀粉样蛋白沉淀疾病。TTR二聚体是一个实验上很难观测到的重要中间体。迄今为止，关于TTR解离过程中的结构变化与分子机制，以及其去折叠的路径等问题仍然缺乏研究。为此，我们利用恒定pH动力学研究了突变L55P以及低pH对TTR二聚体稳定性及去折叠过程的影响。结果表明，酸性环境可以致使TTR结构变的松散，突变则会造成TTR外端结构的破坏。在酸性环境中，L55P二聚体有巨大的结构变化，并有明显的解离趋势。我们的结果表明，strand C的解离将是整个去折叠过程的起点。除此之外，两个单体界面处的氢键对稳定TTR二聚体结构有重要作用。对于TTR二聚体动力学的模拟为研究TTR结构与功能之间的关系提供了有意义的结论，并从微观层面上阐明了TTR二聚体的解离过程。
In recent years, with the development of computational science, moleculardynamics simulation has been widely applicated in biology, chemistry, physics andmaterial. Molecular dynamics simulation can provide detail information of the systemmotions as a function of time, as well as the information of thermodynamic property.Both of them are hardly to be gained from the experiments. To date, the investigation inlife science has gone deep into molecular level. Molecular dynamics simulation iscompletely under the control of scientists, so that by altering specific contributions theirrole in determining a property at atomic level can be known. Thus, this method isplaying an increasingly important role in the study of protein folding/unfolding,molecular recognition, ion transport, and enzyme catalyzed reaction mechanism. In thisdissertation, we investigated several important biological macromolecules by means ofmolecular dynamics simulation method, mainly included the following parts:
1. Exploring the Molecular Basis of dsRNA Recognition by Mss116p UsingMolecular Dynamics Simulations and Free-Energy Calculations
DEAD-box proteins are the largest family of helicase that are important in nearlyall aspects of RNA metabolism. However, it is unclear how these proteins recognize andbind RNA. Here, we present a detailed analysis of the related DEAD-box proteinMss116p-RNA interaction, using molecular dynamics simulations with MM-GBSAcalculations. The energetic analysis indicates that the two strands of double strandsRNA (dsRNA) are recognized asymmetrically by Mss116p. The strand1of dsRNAprovides the main binding affinity. Meanwhile, the nonpolar interaction provides themain driving force for the binding process. Although the contribution of polarinteraction is small, it is vital in stabilizing the protein RNA interaction. Comparedwith the wild type Mss116p, two studied mutants Q412A and D441A have obviouslyreduced binding free energies with dsRNA because of the decreasing of polarinteraction. Three important residues Lys409, Arg415and Arg438lose their bindingaffinity significantly in mutants. In conclusion, these results complement previousexperiments to advance comprehensive understanding of Mss116p-dsRNA interaction. The results also would provide support for the application of similar approaches to theunderstanding of other DEAD-box protein-RNA complexes.
2. Exploring the mechanism how Marburg virus VP35recognizes and bindsdsRNA by molecular dynamics simulations and free energy calculations
Filoviruses often cause terrible infectious disease which has not been successfullydealt with pharmacologically. All filoviruses encode a unique protein termed VP35which can mask doubled-stranded RNA to deactivate interferon. The interface ofVP35-dsRNA would be a feasible target for structure-based antiviral agent design. Toexplore the essence of VP35-dsRNA interaction, molecular dynamics simulationcombined with MM-GBSA calculations were performed on Marburg virusVP35-dsRNA complex and several mutational complexes. The energetic analysisindicates that nonpolar interactions provide the main driving force for the bindingprocess. Although the intermolecular electrostatic interactions play important roles inVP35-dsRNA interaction, the whole polar interactions are unfavorable for bindingwhich result in a low binding affinity. Compared with wild type VP35, the studiedmutants F228A, R271A and K298A have obviously reduced binding free energies withdsRNA reflecting in the reduction of polar or nonpolar interactions. The results alsoindicate that the loss of binding affinity for one dsRNA strand would abolish the totalbinding affinity. Three important residues Arg271, Arg294and Lys298which makesthe largest contribution for binding in VP35lose their binding affinity significantly inmutants. The uncovering of VP35-dsRNA recognition mechanism will provide someinsights for development of antiviral drug.
3. Molecular dynamic investigations of BioH protein substrate specificity forbiotin synthesis
Pimeloyl-ACP methyl ester, which is long known to be a biotin precursor, is thephysiological substrate of BioH. Azelayl methyl esters conjugated to ACP is also indeedaccepted by BioH with very low rate of hydrolysis. To date, the substrate specificity forBioH and the molecular origin for the experimentally observed rate changes ofhydrolysis by the chain elongation to C9species have remained elusive. To this end, wehave investigated chain elongation effects on the structures by using the fully atomisticmolecular dynamics simulations combined with binding free energy calculations. Theresults indicate that the substrate specificity is determined by BioH together with ACP.The added two methylenes would increase the structural flexibility by protein motionsat the interface of ACP and BioH, instead of making steric clashes with the side chains of the BioH hydrophobic cavity. On the other hand, the slower hydrolysis of azelaylsubstrate is suggested to be associated with the loose of contacts between BioH andACP, and with the lost electrostatic interactions of two ionic/hydrogen bondingnetworks at the interface of the two proteins. The present study provides importantinsights into the structure-function relationships of the complex of BioH withMe-pimeloyl-ACP, which could contribute to further understanding about themechanism of the biotin synthetic pathway, including the catalytic role of BioH.
4. Mutation and low pH effect on the stability as well as unfolding kinetics oftransthyretin dimer
Transthyretin (TTR) dissociation and aggregation appear to cause several amyloiddiseases. TTR dimer is an important intermediate that is hard to be observed from thebiological experiments. To date, the molecular origin and the structural motifs for TTRdimer dissociation, as well as the unfolding process have not been rationalized at atomicresolution. To this end, we have investigated the effect of low pH and mutation L55P onstability as well as the unfolding pathway of TTR dimer using constant pH moleculardynamics simulations. The result shows that acidic environment results in loose TTRdimer structure. Mutation L55P causes the disruption of strand D and makes theCE-loop very flexible. In acidic conditions, dimeric L55P mutant exhibits notableconformation changes and an evident trend to separate. Our work shows that themovements of strand C and the loops nearby are the beginning of unfolding process. Inaddition, hydrogen bond network at the interface of the two monomers plays a part instabilizing TTR dimer. The dynamic investigation on TTR dimer provides importantinsights into the structure-function relationships of TTR, and rationalizes the structuralorigin for the tendency of unfolding and changes of structure that occur uponintroduction of mutation and pH along the TTR dimer dissociation and unfoldingprocess.
1.解旋酶Mss116p对双链RNA的识别机制
DEAD-box蛋白质家族是最大的RNA解旋酶家族，与几乎所有涉及到RNA的领域都密切相关。但是，该类蛋白质识别并结合RNA的具体机制尚不明确。在本文中，我们利用分子动力学模拟与MM-GBSA方法，对DEAD-box的模板蛋白Mss116p与双链RNA之间的相互作用进行了深入研究。结合自由能分析的结果表明：双链RNA的两条链与Mss116p的结合活性是不相等的。其中的一条链提供了主要的结合活性，而另一条链与蛋白质几乎没有任何结合活性。同时，在Mss116p与双链RNA的结合过程中，非极性相互作用提供了主要的结合驱动力。虽然极性相互作用对于结合的贡献很小，但它在稳定蛋白质-RNA相互作用时也有着重要作用。与野生型的Mss116p相比，两种突变体，Q412A与D441A与dsRNA的结合自由能有明显的降低，其主要原因是极性相互作用的减少。三个重要的氨基酸残基Lys409,Arg415以及Arg438在突变体中都丧失了结合活性。总的来说，上述结论对实验进行了很好的补充，有助于人们更全面的理解Mss116p的解旋机理。同时，本文中方法的应用也可以推广到DEAD-box家族的其它蛋白质上，用以研究它们的识别机制。
2.马尔堡病毒蛋白VP35对双链RNA的识别机制
线状病毒经常会造成非常严重的传染病，而人们至今依然没有找到有效的药物。所有的线状病毒都可以编码一种叫VP35的蛋白，这种蛋白可以隐藏病毒的遗传物质双链RNA，以此逃脱人体的免疫系统。因此，VP35与双链RNA的接触面将是一个较为可信抗病毒药物设计的靶点。为了研究VP35与双链RNA的识别机制，我们采取了分子动力学模拟与MM-GBSA方法去研究VP35与双链RNA的复合物，并同时研究了几个突变体复合物。能量分析的结果表明非极性相互作用提供了结合的主要驱动力。虽然分子间静电力在VP35与双链RNA的结合中起了非常重要的作用，但整体的极性相互作用却是不利于两者的结合，这也导致了整体结合活性偏低。与野生型VP35相比，三个突变体F228A,R271A与K298A与双链RNA的结合能力有明显的降低。同时，分析结果也表明如果一条RNA链与VP35失去了结合活性，那么整个双链RNA都将与VP35失去结合活性。同时我们还确定了结合过程中最重要的三个残基，Arg271,Arg294以及Lys298，这三个残基在突变体中都失去了结合活性。我们对VP35与双链RNA结合机制的研究成果将有助于开发新的抗病毒药物。
3.维生素H合成过程中BioH的底物特异性研究
众所周知，庚二酰甲酯-ACP复合物是维生素H的前驱化合物，也是其合成过程中的酶BioH的生理底物。而壬二酰甲酯与ACP的复合物也可以被BioH所催化，但是其水解速率非常低。迄今为止，人们对于BioH的底物特异性，以及将庚二酰甲酯的C7链延长到C9之后，水解速率降低的原因还不清楚。为此，我们利用分子动力学模拟与结合自由能计算，研究了碳链伸长对BioH底物结合造成的影响。我们的结果表明底物特异性是由BioH与ACP共同决定的。增加的两个碳的碳链将不会与BioH的疏水空腔产生位阻，而是会造成ACP与BioH接触面上结构的变化。从另一方面说，壬二酰底物过低的水解速率也与BioH及ACP之间结合能力的减弱有关，主要是体现在接触面上两个主要的盐桥、氢键网络的破坏。本文的研究为BioH与庚二酰甲酯-ACP复合物的结构与功能提供了重要的数据，为全面的理解BioH的催化机理奠定了理论基础。
4.突变及低pH环境对transthyretin二聚体稳定性及去折叠机制的影响
Transthyretin的解离与聚集可以引发数种淀粉样蛋白沉淀疾病。TTR二聚体是一个实验上很难观测到的重要中间体。迄今为止，关于TTR解离过程中的结构变化与分子机制，以及其去折叠的路径等问题仍然缺乏研究。为此，我们利用恒定pH动力学研究了突变L55P以及低pH对TTR二聚体稳定性及去折叠过程的影响。结果表明，酸性环境可以致使TTR结构变的松散，突变则会造成TTR外端结构的破坏。在酸性环境中，L55P二聚体有巨大的结构变化，并有明显的解离趋势。我们的结果表明，strand C的解离将是整个去折叠过程的起点。除此之外，两个单体界面处的氢键对稳定TTR二聚体结构有重要作用。对于TTR二聚体动力学的模拟为研究TTR结构与功能之间的关系提供了有意义的结论，并从微观层面上阐明了TTR二聚体的解离过程。
In recent years, with the development of computational science, moleculardynamics simulation has been widely applicated in biology, chemistry, physics andmaterial. Molecular dynamics simulation can provide detail information of the systemmotions as a function of time, as well as the information of thermodynamic property.Both of them are hardly to be gained from the experiments. To date, the investigation inlife science has gone deep into molecular level. Molecular dynamics simulation iscompletely under the control of scientists, so that by altering specific contributions theirrole in determining a property at atomic level can be known. Thus, this method isplaying an increasingly important role in the study of protein folding/unfolding,molecular recognition, ion transport, and enzyme catalyzed reaction mechanism. In thisdissertation, we investigated several important biological macromolecules by means ofmolecular dynamics simulation method, mainly included the following parts:
1. Exploring the Molecular Basis of dsRNA Recognition by Mss116p UsingMolecular Dynamics Simulations and Free-Energy Calculations
DEAD-box proteins are the largest family of helicase that are important in nearlyall aspects of RNA metabolism. However, it is unclear how these proteins recognize andbind RNA. Here, we present a detailed analysis of the related DEAD-box proteinMss116p-RNA interaction, using molecular dynamics simulations with MM-GBSAcalculations. The energetic analysis indicates that the two strands of double strandsRNA (dsRNA) are recognized asymmetrically by Mss116p. The strand1of dsRNAprovides the main binding affinity. Meanwhile, the nonpolar interaction provides themain driving force for the binding process. Although the contribution of polarinteraction is small, it is vital in stabilizing the protein RNA interaction. Comparedwith the wild type Mss116p, two studied mutants Q412A and D441A have obviouslyreduced binding free energies with dsRNA because of the decreasing of polarinteraction. Three important residues Lys409, Arg415and Arg438lose their bindingaffinity significantly in mutants. In conclusion, these results complement previousexperiments to advance comprehensive understanding of Mss116p-dsRNA interaction. The results also would provide support for the application of similar approaches to theunderstanding of other DEAD-box protein-RNA complexes.
2. Exploring the mechanism how Marburg virus VP35recognizes and bindsdsRNA by molecular dynamics simulations and free energy calculations
Filoviruses often cause terrible infectious disease which has not been successfullydealt with pharmacologically. All filoviruses encode a unique protein termed VP35which can mask doubled-stranded RNA to deactivate interferon. The interface ofVP35-dsRNA would be a feasible target for structure-based antiviral agent design. Toexplore the essence of VP35-dsRNA interaction, molecular dynamics simulationcombined with MM-GBSA calculations were performed on Marburg virusVP35-dsRNA complex and several mutational complexes. The energetic analysisindicates that nonpolar interactions provide the main driving force for the bindingprocess. Although the intermolecular electrostatic interactions play important roles inVP35-dsRNA interaction, the whole polar interactions are unfavorable for bindingwhich result in a low binding affinity. Compared with wild type VP35, the studiedmutants F228A, R271A and K298A have obviously reduced binding free energies withdsRNA reflecting in the reduction of polar or nonpolar interactions. The results alsoindicate that the loss of binding affinity for one dsRNA strand would abolish the totalbinding affinity. Three important residues Arg271, Arg294and Lys298which makesthe largest contribution for binding in VP35lose their binding affinity significantly inmutants. The uncovering of VP35-dsRNA recognition mechanism will provide someinsights for development of antiviral drug.
3. Molecular dynamic investigations of BioH protein substrate specificity forbiotin synthesis
Pimeloyl-ACP methyl ester, which is long known to be a biotin precursor, is thephysiological substrate of BioH. Azelayl methyl esters conjugated to ACP is also indeedaccepted by BioH with very low rate of hydrolysis. To date, the substrate specificity forBioH and the molecular origin for the experimentally observed rate changes ofhydrolysis by the chain elongation to C9species have remained elusive. To this end, wehave investigated chain elongation effects on the structures by using the fully atomisticmolecular dynamics simulations combined with binding free energy calculations. Theresults indicate that the substrate specificity is determined by BioH together with ACP.The added two methylenes would increase the structural flexibility by protein motionsat the interface of ACP and BioH, instead of making steric clashes with the side chains of the BioH hydrophobic cavity. On the other hand, the slower hydrolysis of azelaylsubstrate is suggested to be associated with the loose of contacts between BioH andACP, and with the lost electrostatic interactions of two ionic/hydrogen bondingnetworks at the interface of the two proteins. The present study provides importantinsights into the structure-function relationships of the complex of BioH withMe-pimeloyl-ACP, which could contribute to further understanding about themechanism of the biotin synthetic pathway, including the catalytic role of BioH.
4. Mutation and low pH effect on the stability as well as unfolding kinetics oftransthyretin dimer
Transthyretin (TTR) dissociation and aggregation appear to cause several amyloiddiseases. TTR dimer is an important intermediate that is hard to be observed from thebiological experiments. To date, the molecular origin and the structural motifs for TTRdimer dissociation, as well as the unfolding process have not been rationalized at atomicresolution. To this end, we have investigated the effect of low pH and mutation L55P onstability as well as the unfolding pathway of TTR dimer using constant pH moleculardynamics simulations. The result shows that acidic environment results in loose TTRdimer structure. Mutation L55P causes the disruption of strand D and makes theCE-loop very flexible. In acidic conditions, dimeric L55P mutant exhibits notableconformation changes and an evident trend to separate. Our work shows that themovements of strand C and the loops nearby are the beginning of unfolding process. Inaddition, hydrogen bond network at the interface of the two monomers plays a part instabilizing TTR dimer. The dynamic investigation on TTR dimer provides importantinsights into the structure-function relationships of TTR, and rationalizes the structuralorigin for the tendency of unfolding and changes of structure that occur uponintroduction of mutation and pH along the TTR dimer dissociation and unfoldingprocess.
引文
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