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Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2021-12-30 , DOI: 10.1021/acs.jpcb.1c08525 Murilo N Sanches 1 , Kaitlin Knapp 2 , Antonio B Oliveira 2 , Peter G Wolynes 2 , José N Onuchic 2, 3 , Vitor B P Leite 1
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2021-12-30 , DOI: 10.1021/acs.jpcb.1c08525 Murilo N Sanches 1 , Kaitlin Knapp 2 , Antonio B Oliveira 2 , Peter G Wolynes 2 , José N Onuchic 2, 3 , Vitor B P Leite 1
Affiliation
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The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer’s disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.
中文翻译：
使用能量景观可视化方法检查淀粉样蛋白-β 单体变体的集合及其形成纤维的倾向
淀粉样蛋白-β (Aβ) 单体是一种本质上无序的肽，由淀粉样蛋白前体蛋白的切割产生，导致 Aβ-40 和 Aβ-42 作为主要产物。这两种亚型产生病理聚集体，其积累与阿尔茨海默病 (AD) 相关。实验表明，尽管 Aβ-42 的自然丰度小于 Aβ-40，但与 Aβ-40 相比，Aβ-42 更容易聚集。此外，一些单点突变与 AD 的早发形式有关。这项工作分析了正常 Aβ-40 和 Aβ-42 单体的粗粒度联想记忆、水介导的结构和能量模型 (AWSEM) 模拟，以及与早发性疾病相关的六个单点突变。我们使用能源景观可视化方法（ELViM）分析了模拟，一种无反应坐标的方法，适合探索本质上无序蛋白质的受挫能量景观。ELViM 被证明可以区分快速形成纤维的变体的单体集合和不那么容易形成纤维的变体。它还描绘了表征每个集合的氨基酸接触。结果揭示了 ELViM 探测内在无序蛋白质的潜力。
更新日期：2022-01-13
中文翻译：
使用能量景观可视化方法检查淀粉样蛋白-β 单体变体的集合及其形成纤维的倾向
淀粉样蛋白-β (Aβ) 单体是一种本质上无序的肽，由淀粉样蛋白前体蛋白的切割产生，导致 Aβ-40 和 Aβ-42 作为主要产物。这两种亚型产生病理聚集体，其积累与阿尔茨海默病 (AD) 相关。实验表明，尽管 Aβ-42 的自然丰度小于 Aβ-40，但与 Aβ-40 相比，Aβ-42 更容易聚集。此外，一些单点突变与 AD 的早发形式有关。这项工作分析了正常 Aβ-40 和 Aβ-42 单体的粗粒度联想记忆、水介导的结构和能量模型 (AWSEM) 模拟，以及与早发性疾病相关的六个单点突变。我们使用能源景观可视化方法（ELViM）分析了模拟，一种无反应坐标的方法，适合探索本质上无序蛋白质的受挫能量景观。ELViM 被证明可以区分快速形成纤维的变体的单体集合和不那么容易形成纤维的变体。它还描绘了表征每个集合的氨基酸接触。结果揭示了 ELViM 探测内在无序蛋白质的潜力。
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