Computational Investigation of the Binding Dynamics of Oligo p-Phenylene Ethynylene Fluorescence Sensors and Aβ Oligomers.
Computational Investigation of the Binding Dynamics of Oligo p-Phenylene Ethynylene Fluorescence Sensors and Aβ Oligomers.
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寡苯基乙烯乙烯荧光传感器和Aβ低聚物的结合动力学的计算研究。
DOI：
10.1021/acschemneuro.0c00360
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发表时间：
2020-11-18
影响因子：
5
通讯作者：
Evans DG
中科院分区：
文献类型：
--
作者：
Martin TD;Brinkley G;Whitten DG;Chi EY;Evans DG
淀粉样蛋白聚集体是神经退行性疾病如阿尔茨海默病（AD）和帕金森病（PD）的病理学标志，并且被认为在神经退行性疾病和认知障碍发作之前形成。因此，监测蛋白质聚集的过程对于理解和对抗这些疾病至关重要。我们最近证明了一类新型的荧光传感器，低聚对亚苯基乙炔（PE）基电解质（OPEs）选择性地结合并检测AD相关淀粉样β（Aβ）肽的前纤维和纤维聚集体，而不是单体Aβ。在这项研究中，我们使用经典的全原子分子动力学模拟研究了两种OPEs（阴离子OPE 12 −和阳离子OPE 24+）与两种不同的富含β折叠的Aβ寡聚体之间的结合。我们的模拟揭示了Aβ寡聚体表面上的许多OPE结合位点，这些位点具有疏水氨基酸以及带相反电荷的氨基酸。结合能计算表明阴离子和阳离子OPEs与Aβ寡聚体之间存在能量有利的相互作用。此外，OPEs作为复合物以及单个分子结合。与游离OPEs相比，Aβ原纤维结合的OPEs显示出主链平面化，具有受限的旋转和减少的乙酯端基的水合。这些特征，沿着OPE络合，与已知的结合诱导的OPE荧光开启机制和从水溶液中猝灭的未结合状态的光谱偏移一致。因此，这项研究揭示了OPE-Aβ原纤维相互作用的分子水平细节，并为OPEs的荧光开启传感模式提供了结构基础。
Amyloid protein aggregates are pathological hallmarks of neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD) diseases and are believed to be formed well before the onset of neurodegeneration and cognitive impairment. Monitoring the course of protein aggregation is thus vital to understanding and combating these diseases. We have recently demonstrated that a novel class of fluorescence sensors, oligomeric p-phenylene ethynylene (PE)-based electrolytes (OPEs) selectively bind to and detect pre-fibrillar and fibrillar aggregates of AD-related amyloid-β (Aβ) peptides over monomeric Aβ. In this study, we investigated the binding between two OPEs, anionic OPE12− and cationic OPE24+, and to two different β-sheet rich Aβ oligomers using classical all-atom molecular dynamics simulations. Our simulations have revealed a number of OPE binding sites on Aβ oligomer surface and these sites feature hydrophobic amino acids as well as oppositely charged amino acids. Binding energy calculations show energetically favorable interactions between both anionic and cationic OPEs with Aβ oligomers. Moreover, OPEs bind as complexes as well as single molecules. Compared to free OPEs, Aβ protofibril bound OPEs show backbone planarization with restricted rotations and reduced hydration of the ethyl ester end groups. These characteristics, along with OPE complexation, align with known mechanisms of binding induced OPE fluorescence turn-on and spectral shifts from a quenched, unbound state in aqueous solutions. This study thus sheds light on the molecular-level details of OPE-Aβ protofibril interactions and provides a structural basis for fluorescence turn-on sensing modes of OPEs.
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DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Biancalana M;Koide S
通讯作者：
Koide S
影响因子：
4.1
作者：
Donabedian PL;Evanoff M;Monge FA;Whitten DG;Chi EY
通讯作者：
Chi EY
DOI：
10.1039/c0cp00111b
发表时间：
2010-07-28
期刊：
Physical chemistry chemical physics : PCCP
影响因子：
--
作者：
Dupradeau FY;Pigache A;Zaffran T;Savineau C;Lelong R;Grivel N;Lelong D;Rosanski W;Cieplak P
通讯作者：
Cieplak P
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1186/alzrt226
发表时间：
2013
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Hayden EY;Teplow DB
通讯作者：
Teplow DB