Pyroglutamylation modulates electronic properties and the conformational ensemble of the amyloid β-peptide.

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-07-01 Epub Date: 2024-03-04 DOI:10.1002/prot.26677
Darcy S Davidson, Justin A Lemkul
{"title":"Pyroglutamylation modulates electronic properties and the conformational ensemble of the amyloid β-peptide.","authors":"Darcy S Davidson, Justin A Lemkul","doi":"10.1002/prot.26677","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the formation of extracellular amyloid-β (Aβ) plaques. The underlying cause of AD is unknown, however, post-translational modifications (PTMs) of Aβ have been found in AD patients and are thought to play a role in protein aggregation. One such PTM is pyroglutamylation, which can occur at two sites in Aβ, Glu3 and Glu11. This modification of Aβ involves the truncation and charge-neutralization of N-terminal glutamate, causing Aβ to become more hydrophobic and prone to aggregation. The molecular mechanism by which the introduction of pyroglutamate (pE) promotes aggregation has not been determined. To gain a greater understanding of the role that charge neutralization and truncation of the N-terminus plays on Aβ conformational sampling, we used the Drude polarizable force field (FF) to perform molecular dynamics simulations on Aβ<sub>pE3-42</sub> and Aβ<sub>pE11-42</sub> and comparing their properties to previous simulations of Aβ<sub>1-42</sub>. The Drude polarizable FF allows for a more accurate representation of electrostatic interactions, therefore providing novel insights into the role that charge plays in protein dynamics. Here, we report the parametrization of pE in the Drude polarizable FF and the effect of pyroglutamylation on Aβ. We found that Aβ<sub>pE3-42</sub> and Aβ<sub>pE11-42</sub> alter the permanent and induced dipoles of the peptide. Specifically, we found that Aβ<sub>pE3-42</sub> and Aβ<sub>pE11-42</sub> have modification-specific backbone and sidechain polarization response and perturbed solvation properties that shift the Aβ conformational ensemble.</p>","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11147713/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Electronic Materials","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/prot.26677","RegionNum":3,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ENGINEERING, ELECTRICAL & ELECTRONIC","Score":null,"Total":0}
引用次数: 0

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the formation of extracellular amyloid-β (Aβ) plaques. The underlying cause of AD is unknown, however, post-translational modifications (PTMs) of Aβ have been found in AD patients and are thought to play a role in protein aggregation. One such PTM is pyroglutamylation, which can occur at two sites in Aβ, Glu3 and Glu11. This modification of Aβ involves the truncation and charge-neutralization of N-terminal glutamate, causing Aβ to become more hydrophobic and prone to aggregation. The molecular mechanism by which the introduction of pyroglutamate (pE) promotes aggregation has not been determined. To gain a greater understanding of the role that charge neutralization and truncation of the N-terminus plays on Aβ conformational sampling, we used the Drude polarizable force field (FF) to perform molecular dynamics simulations on AβpE3-42 and AβpE11-42 and comparing their properties to previous simulations of Aβ1-42. The Drude polarizable FF allows for a more accurate representation of electrostatic interactions, therefore providing novel insights into the role that charge plays in protein dynamics. Here, we report the parametrization of pE in the Drude polarizable FF and the effect of pyroglutamylation on Aβ. We found that AβpE3-42 and AβpE11-42 alter the permanent and induced dipoles of the peptide. Specifically, we found that AβpE3-42 and AβpE11-42 have modification-specific backbone and sidechain polarization response and perturbed solvation properties that shift the Aβ conformational ensemble.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
焦谷氨酰化改变了淀粉样β肽的电子特性和构象组合。
阿尔茨海默病(AD)是一种神经退行性疾病,其特征是细胞外淀粉样蛋白-β(Aβ)斑块的形成。注意力缺失症的根本原因尚不清楚,但在注意力缺失症患者中发现了 Aβ 的翻译后修饰(PTM),并认为这种修饰在蛋白质聚集中起了作用。其中一种 PTM 是焦谷氨酰化,可发生在 Aβ 的两个位点,即 Glu3 和 Glu11。Aβ 的这种修饰涉及 N 端谷氨酸的截断和电荷中和,从而使 Aβ 变得更加疏水和容易聚集。引入焦谷氨酸(pE)促进聚集的分子机制尚未确定。为了更深入地了解电荷中和以及 N 端截断对 Aβ 构象取样的作用,我们使用 Drude 可极化力场(FF)对 AβpE3-42 和 AβpE11-42 进行了分子动力学模拟,并将它们的特性与之前对 Aβ1-42 的模拟进行了比较。Drude 可极化 FF 能够更准确地表示静电相互作用,因此为了解电荷在蛋白质动力学中的作用提供了新的视角。在此,我们报告了 pE 在 Drude 可极化 FF 中的参数化以及焦谷氨酰化对 Aβ 的影响。我们发现 AβpE3-42 和 AβpE11-42 改变了肽的永久偶极和诱导偶极。具体来说,我们发现 AβpE3-42 和 AβpE11-42 具有特定修饰的骨架和侧链极化响应以及扰动的溶解特性,从而改变了 Aβ 的构象组合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
期刊最新文献
Hyperbaric oxygen treatment promotes tendon-bone interface healing in a rabbit model of rotator cuff tears. Oxygen-ozone therapy for myocardial ischemic stroke and cardiovascular disorders. Comparative study on the anti-inflammatory and protective effects of different oxygen therapy regimens on lipopolysaccharide-induced acute lung injury in mice. Heme oxygenase/carbon monoxide system and development of the heart. Hyperbaric oxygen for moderate-to-severe traumatic brain injury: outcomes 5-8 years after injury.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1