...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Effects of Point Substitutions on the Structure of Toxic Alzheimer's β-Amyloid Channels: Atomic Force Microscopy and Molecular Dynamics Simulations
【24h】

Effects of Point Substitutions on the Structure of Toxic Alzheimer's β-Amyloid Channels: Atomic Force Microscopy and Molecular Dynamics Simulations

机译：点取代对有毒阿尔茨海默氏症β-淀粉样蛋白通道结构的影响：原子力显微镜和分子动力学模拟

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Alzheimer's disease (AD) is a misfolded protein disease characterized by the accumulation of β-amyloid (Aβ) peptide as senile plaques, progressive neurodegeneration, and memory loss. Recent evidence suggests that AD pathology is linked to the destabilization of cellular ionic homeostasis mediated by toxic pores made of Aβ peptides. Understanding the exact nature by which these pores conduct electrical and molecular signals could aid in identifying potential therapeutic targets for the prevention and treatment of AD. Here using atomic force microscopy (AFM) and molecular dynamics (MD) simulations, we compared the imaged pore structures with models to predict channel conformations as a function of amino acid sequence. Site-specific amino acid (AA) substitutions in the wild-type Aβ_(1_42) peptide yield information regarding the location and significance of individual AA residues to its characteristic structure-activity relationship. We selected two AAs that our MD simulation predicted to inhibit or permit pore conductance. The substitution of Phe 19 with Pro has previously been shown to eliminate conductance in the planar lipid bilayer system. Our MD simulations predict a channel-like shape with a collapsed pore, which is supported by the AFM channel images. We suggest that proline, a known β-sheet breaker, creates a kink in the center of the pore and prevents conductance via blockage. This residue may be a viable target for drug development studies aiming to inhibit Ati from inducing ionic destabilization toxicity. The substitution of Phe20 with Cys exhibits pore structures indistinguishable from the wild type in AFM images. MD simulations predict site 20 to face the solvated pore. Overall, the mutations support the previously predicted β-sheet-based channel structure.
机译：阿尔茨海默氏病（AD）是一种折叠错误的蛋白质疾病，其特征是β-淀粉样蛋白（Aβ）肽以老年斑的形式积累，进行性神经变性和记忆力减退。最近的证据表明，AD病理与由Aβ肽制成的有毒孔介导的细胞离子稳态的失稳有关。了解这些毛孔传导电和分子信号的确切性质可以帮助确定预防和治疗AD的潜在治疗靶标。在这里，使用原子力显微镜（AFM）和分子动力学（MD）模拟，我们将成像的孔结构与模型进行了比较，以预测通道构象随氨基酸序列的变化。野生型Aβ_（1_42）肽中的位点特异性氨基酸（AA）置换产生有关单个AA残基的位置和重要性与其特征性结构-活性关系的信息。我们选择了两个MD预测可以抑制或允许孔隙电导的AA。以前已证明用Pro取代Phe 19可消除平面脂质双层系统中的电导。我们的MD模拟预测出具有塌陷孔的类似通道的形状，这由AFM通道图像支持。我们建议脯氨酸（一种已知的β-折叠阻滞剂）会在毛孔中心产生扭结，并通过阻塞来防止电导。该残留物可能是药物开发研究的可行目标，旨在抑制Ati诱导离子去稳定毒性。用Cys取代Phe20，在AFM图像中显示出与野生型无法区分的孔结构。 MD模拟预测部位20面对溶剂化的孔。总的来说，突变支持先前预测的基于β-折叠的通道结构。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号