Modeling of amyloid peptides and proteins

淀粉样肽和蛋白质的建模

• 批准号: 7338817
• 负责人: HOMER ROBERT GUY
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338817
• 关键词: Modeling; amyloid; peptides; proteins

It used to be thought that Alzheimer's disease was caused by fibrils formed primarily by alyloid beta (Abeta) peptides of 40 or 42 residues. However, numerous recent studies indicate that smaller oligomeric assemblies of Abeta are responsible for inhibition of long-term potentiation associated with short-term memory loss, and for neurotoxic properties that cause cell death. Several recent studies also indicate that neurotoxity involves interactions with membranes and have supported initial findings of our collaborators that Abeta peptides form transmembrane ion channels. Abeta peptides form many different types of assemblies and even the secondary structure of the peptides depends upon its environment and concentration, and often changes with time. For example, solution NMR studies of Abeta monomers in apolar solvent studies have identified two a-helical segments; whereas, solid state NMR studies of fibrils indicate that the same two segments form a strands that assemble into parallel a sheets. The peptide assembly process that leads to fibrils is very slow, in some cases taking days to occur, and is preceded by formation of a variety of smaller oligomers and protofibrils. We are using molecular modeling and simulations to better understand the structures of these oligomers and how they assemble. We have constructed the following types of soluble assemblies: dimers, trimers, tetramers, hexamers, strings of hexamers, dodecamers, AbetaOs (18 subunits), annular protofibril (36 subunits), HMW oligomers (72 subunits), protofibrils with mass-per-lengths of 18 and 27kDa/nm, and two-dimensional hexagonal lattices that can extend indefinitely. We have also developed numerous models in which Abeta peptides form large assemblies on the membrane surface and then insert through the membrane to form channels. Assemblies with dimensions and masses of both soluble and membrane-bound models have been observed in microscopy and biochemical studies. Most of our models of the large assemblies involve hexamers in which the C-termini segments (residues 29-40 or 29-42) form a six-stranded antiparallel a barrel. We have also simulated how some of these assemblies could morph or grow into models of models of fibrils that are based on solid state NMR results. The PrP prion protein can exist in two forms, the normal PrPC form and a toxic PrPSc form that causes the Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, scrapie, and other spongiform encephalopathies. Aspects of the PrP and PrP-associated diseases resemble those of Abeta and Alzheimer's. The most hydrophobic portion of the 230 residue-long PrP protein has a sequence quite similar to the hydrophobic segment of Abeta that we propose to form a a barrel. PrPSc has been shown to assemble into a hexagonal lattice and into fibrils. We have constructed PrP models with the axis of the putative a barrel on one of the 3-fold axes of the lattice (similar to our hexagonal lattice models of Abeta). Experimental studies indicate that PrP protein can span membranes and may interact with Abeta peptides. We have constructed models in which the PrP a barrels span the lipid bilayer and in which a hexagonal lattice structure contains both PrP and Abeta.

过去人们认为，阿尔茨海默病是由主要由40或42个残基的β (β)多肽形成的原纤维引起的。然而，最近的许多研究表明，较小的Abeta寡聚体组装负责抑制与短期记忆丧失相关的长期增强，以及导致细胞死亡的神经毒性。最近的几项研究也表明，神经毒性涉及与膜的相互作用，并支持了我们合作者的初步发现，即β肽形成跨膜离子通道。β肽形成许多不同类型的组装，甚至肽的二级结构取决于其环境和浓度，并经常随时间变化。例如，在极性溶剂研究中，β单体的溶液核磁共振研究已经确定了两个a-螺旋段；然而，对原纤维的固态核磁共振研究表明，相同的两个片段形成一条链，组装成平行的a片。导致原纤维的肽组装过程非常缓慢，在某些情况下需要几天才能发生，并且在形成各种较小的低聚物和原原纤维之前。我们正在使用分子模型和模拟来更好地理解这些低聚物的结构以及它们是如何组装的。我们构建了以下类型的可溶性组合：二聚体、三聚体、四聚体、六聚体、六聚体串、十二聚体、AbetaOs（18个亚基）、环状原纤维（36个亚基）、HMW低聚物（72个亚基）、质量/长度为18和27kDa/nm的原纤维，以及可以无限延伸的二维六边形晶格。我们还开发了许多模型，其中β肽在膜表面形成大的组装，然后通过膜插入形成通道。在显微镜和生化研究中已经观察到具有可溶性和膜结合模型的尺寸和质量的组装。我们的大多数大型组合体模型涉及六聚体，其中c端片段（残基29-40或29-42）形成六股反平行的桶状结构。我们还模拟了其中一些组件如何变形或生长成基于固态核磁共振结果的原纤维模型的模型。PrP朊蛋白可以以两种形式存在，正常的PrPC形式和导致克雅氏病、牛海绵状脑病、痒病和其他海绵状脑病的有毒PrPSc形式。PrP和PrP相关疾病的一些方面类似于β和阿尔茨海默病。在230个残基长的PrP蛋白中，最疏水部分的序列与我们提出的Abeta疏水片段非常相似，形成了一个桶状结构。PrPSc已被证明可以组装成六边形晶格和原纤维。我们已经构建了PrP模型，假定桶的轴在晶格的三重轴之一上（类似于我们的Abeta六边形晶格模型）。实验研究表明，PrP蛋白可以跨越膜，并可能与β肽相互作用。我们已经构建了模型，其中PrP桶跨越脂质双分子层，其中六边形晶格结构包含PrP和β。