Modeling of amyloid peptides and proteins

过去认为阿尔茨海默病是由主要由40或42个残基的类淀粉β（Abeta）肽形成的原纤维引起的。然而，许多最近的研究表明，较小的寡聚体组装的Abeta负责抑制与短期记忆丧失相关的长时程增强，并导致细胞死亡的神经毒性特性。最近的几项研究也表明，神经毒性涉及与膜的相互作用，并支持我们的合作者的初步发现，Abeta肽形成跨膜离子通道。Abeta肽形成许多不同类型的组装体，甚至肽的二级结构也取决于其环境和浓度，并且经常随时间而变化。例如，Abeta单体在非极性溶剂中的溶液NMR研究已经鉴定出两个α-螺旋片段;而原纤维的固态NMR研究表明，相同的两个片段形成组装成平行α片的α链。导致原纤维的肽组装过程非常缓慢，在某些情况下需要数天才能发生，并且在此之前形成各种较小的寡聚体和原纤维。我们正在使用分子建模和模拟来更好地了解这些低聚物的结构以及它们是如何组装的。我们已经构建了以下类型的可溶性组装体：二聚体、三聚体、四聚体、六聚体、六聚体串、十二聚体、AbetaO（18个亚基）、环状原纤维（36个亚基）、HMW寡聚体（72个亚基）、每长度质量为18和27 kDa/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Abeta肽在膜表面形成大的组装体，然后插入膜形成通道。在显微镜和生物化学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件。我们的大部分模型的大型组件涉及六聚体，其中C-末端片段（残基29-40或29-42）形成一个六链反平行桶。我们还模拟了这些组件中的一些如何变形或生长成基于固态NMR结果的原纤维模型的模型。PrP朊病毒蛋白可以以两种形式存在，正常PrPC形式和导致克雅氏病、牛海绵状脑病、瘙痒症和其他海绵状脑病的毒性PrPSc形式。PrP和PrP相关疾病的方面类似于Abeta和阿尔茨海默氏症。230个残基长的PrP蛋白的最疏水部分具有与我们提出形成桶的Abeta的疏水部分非常相似的序列。已显示PrPSc组装成六方晶格和原纤维。我们已经构建了PrP模型，其假定的桶的轴位于晶格的3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蛋白可以跨膜，并可能与Abeta肽相互作用。我们已经构建了模型，其中的PrP桶跨越脂质双层，其中六方晶格结构包含PrP和Abeta。

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.