淀粉样蛋白分子聚集的全原子分子模拟研究
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摘要
蛋白质分子是组成生物体结构、行使生物学功能的主要生物大分子。通常情况下,蛋白质需要折叠到特定的三维立体结构才能正确行使其生物学功能,而错误的折叠则会导致功能的丧失,并可能引起疾病。例如,阿尔茨海默症、帕金森症、疯牛病等一系列神经退行性疾病就是由于相关蛋白质的错误折叠和病理性聚集所致。因此,理解蛋白质的错误折叠和病理性聚集的分子机制是抑制和治疗相关疾病的关键,是分子生物物理领域人们关注的焦点问题之一
Amyloid-β (Aβ)是链长为37-43个残基的多肽。在阿尔茨海默症的致病过程中,Aβ由可溶性单体聚集为寡聚体,并进而聚集成淀粉样纤维沉淀物。在这种淀粉样纤维聚集体中,以β片为主要构象的Aβ通过链间氢键以及输水相互作用自组装成有序的聚集体。而这种寡聚体／淀粉样纤维聚集体会对神经元细胞产生毒性,从而引起脑损害,并引起疾病。Aβ的聚集过程受到一系列复杂物理化学因素的调控。本论文中,作者从原子层次的物理相互作用出发,通过大量的全原子分子模拟,探索了与阿尔茨海默症密切相关的Amyloid-β (Aβ)的聚集机制,并着重探讨了一些常规的物理化学因素、如结构模板、pH环境等对Aβ病理性聚集的可能调控机制。主要研究内容和结果包括：
一、最近的实验研究表明,溶液中预先存在的Aβ聚集物会促进可溶性Aβ单体的进一步聚集,即所谓的模板效应。基于副本交换全原子分子模拟,我们研究了Aβ聚集过程模板效应的分子机制。计算结果表明,预先形成的Aβ聚集体结构模板对靠近的Aβ单体构象具有明显的调控作用。特别是Aβ聚集体结构模板能够显著地破坏Aβ单体的链内相互作用,从而使得Aβ单体更易于与模板发生相互作用。这一结果也表明,Aβ聚集体结构模板在聚集的初始阶段就开始对Aβ单体进行调控,降低聚集过程中的能量阻挫。另外,我们的计算发现,这种模板效应是通过非特异相互作用进行的,其中,疏水残基起到了更重要的作用。
二、通过计算机模拟发现,不仅Aβ聚集体结构模板能够促进Aβ单体的聚集倾向性,工工-型糖尿病致病蛋白hIAPP聚集体结构模板也能够显著促进Ap单体的聚集倾向性。这和最近实验上发现的cross-seeding现象是自洽的。特别是,我们的计算结果表明,这种模板效应对模板二级结构的敏感性远强于对模板序列的敏感性。另外,我们发现Aβ单体与Aβ聚集体结构模板两端的相互作用几率存在非对称性,并且这种非对称性是由于模板中β片的扭曲而导致的结构非对称性所引起。这种相互作用的非对称性预示着Aβ的聚集生长过程可能存在方向性,这和最近的实验结果是符合的。
三、目前,人们已经了解到Aβ的聚集过程和聚集体形貌受到pH、金属离子等因素的调控。固相核磁实验数据表明,Aβ42的1-16号残基在纤维聚集体中是处于无规柔性结构的。但是,Aβ1-16片段富含带电残基和组氨酸,因此是金属离子的主要结合位点以及pH的主要调控位点。本论文中,我们模拟了不同组氨酸质子化状态下Aβ的单体构象分布,进而理解pH等对Aβ聚集倾向性的调控。结果显示Aβ1-16片段会影响Aβ17-42片段的构象,并调控Aβ的聚集倾向性。这种作用是通过影响链内非特异相互作用和盐桥来实现的。该结果有助于理解pH等静电环境对Aβ聚集的调控机制。
The misfolding of protein or peptide will lead to amyloid aggregation. The amyloid fibril consists of cross-β conformer and is related to a series of diseases. Aβ is a short peptide with37-43residues. Its accumulation in the brain is the key pathological feature of the Alzheimer's disease. The aggregation process of Aβ is very complicated and modulated by many factors. This thesis reports our studies on the mechanism of some relevant effects.
The Aβ is unstructured in aqueous solvent but rich of β-strands in aggregation conformation. Therefore, the monomeric Aβ undergoes a conformational transformation during the formation of fibrillar. The preformed aggregation-prone conformation can evidently speed up the elongation of the fibrils as if it could be provided as templates of β-strand structure. Using atomistic molecular simulations, we studied the template effects of the preformed structure. The analysis of secondary structure propensity implies that the template with the cross-β structure could induce the formation of β-strand conformations for the monomeric Aβ while the helix template has no such effect. When the template is changed into hIAPP or polyalanine, the enhancement could still be observed. This result shows that this effect strongly depends on the secondary structure of the template peptides but is insensitive to the sequence details. Further analysis shows that the template tends to disrupt the intrapeptide interactions of the monomeric Aβ and reduces the energy frustration, therefore promoting the fibrillar aggregation.. These results uggest that the hydrophobic interactions play a crucial role, providing a better understanding on the molecular mechanism of the docking stage of aggregation.
The conformational distribution of the Aβ monomer and aggregation process could be affected by many physical and chemical factors, such as pH environment and metal ions. N-terminal segment, which includes residues1-16, is disordered in the fibrillar aggregates. Previous simulation works usually overlooked the effect of N-terminal disordered parts on the aggregation and removed it directly in the simulations. Noticeably there are three histidines in the N-terminal disordered region. These histidines are sensitive to pH and metal ions. We perform replica exchange molecular dynamics simulation with different charge states of histidines. Our simulation results demonstrated that the N-terminal disordered part can affect the conformational distributions of the residues17-42. The non-specific contacts and salt bridge could be modulated by the charge states of the histidines. These results are important in understanding the mechanism of the pH value and metal ion regulated A (3fibrillar aggregation.
Amyloid-β (Aβ)是链长为37-43个残基的多肽。在阿尔茨海默症的致病过程中,Aβ由可溶性单体聚集为寡聚体,并进而聚集成淀粉样纤维沉淀物。在这种淀粉样纤维聚集体中,以β片为主要构象的Aβ通过链间氢键以及输水相互作用自组装成有序的聚集体。而这种寡聚体／淀粉样纤维聚集体会对神经元细胞产生毒性,从而引起脑损害,并引起疾病。Aβ的聚集过程受到一系列复杂物理化学因素的调控。本论文中,作者从原子层次的物理相互作用出发,通过大量的全原子分子模拟,探索了与阿尔茨海默症密切相关的Amyloid-β (Aβ)的聚集机制,并着重探讨了一些常规的物理化学因素、如结构模板、pH环境等对Aβ病理性聚集的可能调控机制。主要研究内容和结果包括：
一、最近的实验研究表明,溶液中预先存在的Aβ聚集物会促进可溶性Aβ单体的进一步聚集,即所谓的模板效应。基于副本交换全原子分子模拟,我们研究了Aβ聚集过程模板效应的分子机制。计算结果表明,预先形成的Aβ聚集体结构模板对靠近的Aβ单体构象具有明显的调控作用。特别是Aβ聚集体结构模板能够显著地破坏Aβ单体的链内相互作用,从而使得Aβ单体更易于与模板发生相互作用。这一结果也表明,Aβ聚集体结构模板在聚集的初始阶段就开始对Aβ单体进行调控,降低聚集过程中的能量阻挫。另外,我们的计算发现,这种模板效应是通过非特异相互作用进行的,其中,疏水残基起到了更重要的作用。
二、通过计算机模拟发现,不仅Aβ聚集体结构模板能够促进Aβ单体的聚集倾向性,工工-型糖尿病致病蛋白hIAPP聚集体结构模板也能够显著促进Ap单体的聚集倾向性。这和最近实验上发现的cross-seeding现象是自洽的。特别是,我们的计算结果表明,这种模板效应对模板二级结构的敏感性远强于对模板序列的敏感性。另外,我们发现Aβ单体与Aβ聚集体结构模板两端的相互作用几率存在非对称性,并且这种非对称性是由于模板中β片的扭曲而导致的结构非对称性所引起。这种相互作用的非对称性预示着Aβ的聚集生长过程可能存在方向性,这和最近的实验结果是符合的。
三、目前,人们已经了解到Aβ的聚集过程和聚集体形貌受到pH、金属离子等因素的调控。固相核磁实验数据表明,Aβ42的1-16号残基在纤维聚集体中是处于无规柔性结构的。但是,Aβ1-16片段富含带电残基和组氨酸,因此是金属离子的主要结合位点以及pH的主要调控位点。本论文中,我们模拟了不同组氨酸质子化状态下Aβ的单体构象分布,进而理解pH等对Aβ聚集倾向性的调控。结果显示Aβ1-16片段会影响Aβ17-42片段的构象,并调控Aβ的聚集倾向性。这种作用是通过影响链内非特异相互作用和盐桥来实现的。该结果有助于理解pH等静电环境对Aβ聚集的调控机制。
The misfolding of protein or peptide will lead to amyloid aggregation. The amyloid fibril consists of cross-β conformer and is related to a series of diseases. Aβ is a short peptide with37-43residues. Its accumulation in the brain is the key pathological feature of the Alzheimer's disease. The aggregation process of Aβ is very complicated and modulated by many factors. This thesis reports our studies on the mechanism of some relevant effects.
The Aβ is unstructured in aqueous solvent but rich of β-strands in aggregation conformation. Therefore, the monomeric Aβ undergoes a conformational transformation during the formation of fibrillar. The preformed aggregation-prone conformation can evidently speed up the elongation of the fibrils as if it could be provided as templates of β-strand structure. Using atomistic molecular simulations, we studied the template effects of the preformed structure. The analysis of secondary structure propensity implies that the template with the cross-β structure could induce the formation of β-strand conformations for the monomeric Aβ while the helix template has no such effect. When the template is changed into hIAPP or polyalanine, the enhancement could still be observed. This result shows that this effect strongly depends on the secondary structure of the template peptides but is insensitive to the sequence details. Further analysis shows that the template tends to disrupt the intrapeptide interactions of the monomeric Aβ and reduces the energy frustration, therefore promoting the fibrillar aggregation.. These results uggest that the hydrophobic interactions play a crucial role, providing a better understanding on the molecular mechanism of the docking stage of aggregation.
The conformational distribution of the Aβ monomer and aggregation process could be affected by many physical and chemical factors, such as pH environment and metal ions. N-terminal segment, which includes residues1-16, is disordered in the fibrillar aggregates. Previous simulation works usually overlooked the effect of N-terminal disordered parts on the aggregation and removed it directly in the simulations. Noticeably there are three histidines in the N-terminal disordered region. These histidines are sensitive to pH and metal ions. We perform replica exchange molecular dynamics simulation with different charge states of histidines. Our simulation results demonstrated that the N-terminal disordered part can affect the conformational distributions of the residues17-42. The non-specific contacts and salt bridge could be modulated by the charge states of the histidines. These results are important in understanding the mechanism of the pH value and metal ion regulated A (3fibrillar aggregation.
引文
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