We propose models for in vitro grown mammalian prion protein fibrils based upon left handed beta helices formed both from the N-terminal and C-terminal regions of the proteinase resistant infectious prion core. The C-terminal threading onto a beta-helical structure is almost uniquely determined by fixing the cysteine disulfide bond on a helix corner. In comparison to known left handed helical peptides, the resulting model structures have similar stability attributes including relatively low root mean square deviations in all atom molecular dynamics, substantial side-chain-to-side-chain hydrogen bonding, good volume packing fraction, and low hydrophilic/hydrophobic frustration. For the N-terminus, we propose a new threading of slightly more than two turns, which improves upon the above characteristics relative to existing three turn beta-helical models. The N-terminal and C-terminal beta helices can be assembled into eight candidate models for the fibril repeat units, held together by large hinge (order 30 residues) domain swapping, with three amenable to fibril promoting domain swapping via a small (five residue) hinge on the N-terminal side. Small concentrations of the metastable C-terminal beta helix in vivo might play a significant role in templating the infectious conformation and in enhancing conversion kinetics for inherited forms of the disease and explain resistance (for canines) involving hypothesized coupling to the methionine 129 sulfur known to play a role in human disease.

中文翻译：

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哺乳动物朊病毒原纤维的左手β螺旋模型。


我们提出了基于左手β螺旋的体外生长的哺乳动物朊病毒蛋白原纤维模型，该左手β螺旋由蛋白酶抗性感染性朊病毒核心的N端和C端区域形成。 β-螺旋结构上的 C 端螺纹几乎是通过将半胱氨酸二硫键固定在螺旋角上而唯一确定的。与已知的左手螺旋肽相比，所得的模型结构具有相似的稳定性属性，包括所有原子分子动力学中相对较低的均方根偏差、大量的侧链到侧链氢键、良好的体积堆积分数和低的亲水/疏水挫败。对于 N 末端，我们提出了一种略多于两匝的新螺纹，相对于现有的三匝 β 螺旋模型，它改进了上述特性。 N端和C端β螺旋可以组装成原纤维重复单元的八个候选模型，通过大铰链（30个残基）结构域交换保持在一起，其中三个适合通过小（5个残基）结构域交换促进原纤维结构域交换。 ）铰链位于 N 端侧。体内小浓度的亚稳态 C 端 β 螺旋可能在模板传染性构象和增强疾病遗传形式的转化动力学方面发挥重要作用，并解释涉及与已知的蛋氨酸 129 硫的假设偶联的耐药性（对于犬科动物）。在人类疾病中发挥作用。