有机荧光小分子抑制人胰岛淀粉样多肽破坏细胞膜的机制探究

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• 英文论文题名：Mechanism of Inhibition of Human Islet Amyloid Polypeptide-Induced Membrane Damage by a Small Organic Fluorogen
• 论文作者：李晓旭 ; 万明威 ; 高靓辉 ; 方维海
• 英文论文作者：Xiaoxu Li ; Mingwei Wan ; Lianghui Gao ; Weihai Fang ; Department of Chemistry ; University of Beijing Normal University
• 年：2016
• 作者机构：北京师范大学;
• 论文关键词：耗散粒子动力学(DPD) ; 人胰岛淀粉样多肽(hIAPP) ; 二型糖尿病机制 ; hIAPP毒性抑制剂
• 会议召开时间：2016-07-01
• 会议录名称：中国化学会第30届学术年会摘要集-第十九分会：化学中的量子与经典动力学
• 语种：中文
• 分类号：R587.1
• 学会代码：ZGHY
• 会议名称：中国化学会第30届学术年会-第十九分会 ; 化学中的量子与经典动力学
• 会议地点：中国辽宁大连
• 主办单位：中国化学会
• 学会名称：中国化学会
• 页数：1
• 文件大小：234k
• 原文格式：D
• 会议级别：全国

摘要

人胰岛淀粉样多肽(hIAPP)是导致胰岛β细胞死亡的重要因素,然而在分子水平上hIAPP破坏细胞膜的机制目前尚不明确。我们将应用粗粒化的耗散粒子动力学(DPD)方法模拟磷脂双层膜与α-螺旋结构的hIAPP分子之间的相互作用、探究hIAPP破坏细胞膜的机制。研究结果表明水通道的形成是肽的疏水作用引起的膜表面张力增大和磷脂混乱以及由hIAPP所带电荷引起的电穿孔共同作用的结果。根据该机制,我们推测四苯乙烯的一种衍生物BSPOTPE是保护细胞免受hIAPP毒性破坏的有效抗体。通过模拟我们发现,BSPOTPE分子可以通过疏水吸引和静电吸引作用直接吸附hIAPP螺旋区域的残基,形成疏水内核和亲水外壳明确分离的胶束状的hIAPP-BSPOTPE寡聚体团簇,该团簇通常会保持在膜/水界面而不会插入膜内,降低了hIAPP对膜的吸附程度;BSPOTPE所带负电荷中和了hIAPP所带的正电,阻止了电穿孔作用。通过上述两种方式BSPOTPE可以高效的抑制hIAPP破坏细胞膜。
Human islet amyloid polypeptide(hIAPP) is believed to be responsible for the death of insulin-producing β-cells. However, the mechanism of membrane damage at the molecular level has not been fully elucidated. We employ coarse-grained dissipative particle dynamics simulations to study the interactions between a lipid membrane and hIAPPs with α-helical structures. We demonstrated that the key factor controlling pore formation is the combination of peptide charge-induced electroporation and peptide hydrophobicity-induced lipid disordering and membrane thinning. According to these mechanisms, we suggest that a water-miscible tetraphenylethene BSPOTPE is a potent inhibitor to rescue hIAPP-induced cytotoxicity. Our simulations predict that BSPOTPE molecules can bind directly to the helical regions of hIAPP and form oligomers with separated hydrophobic cores and hydrophilic shells. The micelle-like hIAPP-BSPOTPE clusters tend to be retained in the water/membrane interface and aggregate therein rather than penetrate into the membrane. Electrostatic attraction between BSPOTPE and hIAPP also reduces the extent of hIAPP binding to the anionic lipid bilayer. These two modes work together and efficiently prevent membrane poration.

引文

[1]Kahn,S.E.;Andrikopoulos,S.;Verchere,C.B.Diabetes,1999,48:241.
    [2]Pannuzzo,M.;Raudino,A.;Milardi,D.;La Rosa,C.;Karttunen,M.Sci.Rep.2013,3:2781.
    [3]Zhao,J.;Luo,Y.;Jang,H,;et al.Biochimica et Biophysica Acta(BBA)-Biomembranes,2012,1818:3121.
    [4]Li,X.;Wan,M.;Gao,L.;Fang,W.Scientific reports,2016,6:21614.