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Computational Investigation of the Binding Dynamics of Oligo p-Phenylene Ethynylene Fluorescence Sensors and Aβ Oligomers
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2020-11-03 , DOI: 10.1021/acschemneuro.0c00360
Tye D Martin 1, 2 , Gabriella Brinkley 3 , David G Whitten 2, 4 , Eva Y Chi 2, 4 , Deborah G Evans 5
Affiliation  

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 prefibrillar 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 surfaces, 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.

中文翻译:

低聚对苯乙炔荧光传感器与 Aβ 低聚物的结合动力学的计算研究

淀粉样蛋白聚集体是阿尔茨海默病(AD)和帕金森病(PD)等神经退行性疾病的病理标志,并且被认为是在神经退行性和认知障碍发作之前形成的。因此,监测蛋白质聚集过程对于了解和对抗这些疾病至关重要。我们最近证明了一类新型荧光传感器,即低聚对亚苯基乙炔基 (PE) 电解质 (OPE),它可以选择性地结合并检测 AD 相关淀粉样蛋白 -β (Aβ) 肽的前原纤维和原纤维聚集体,而不是单体 Aβ。在本研究中,我们研究了两种 OPE(阴离子 OPE 1 2–和阳离子 OPE 2 4+)之间的结合,并使用经典的全原子分子动力学模拟得出两种不同的富含 β-折叠的 Aβ 寡聚物。我们的模拟揭示了 Aβ 寡聚物表面上的许多 OPE 结合位点,这些位点具有疏水性氨基酸以及带相反电荷的氨基酸。结合能计算显示阴离子和阳离子 OPE 与 Aβ 低聚物之间存在有利的能量相互作用。此外,OPE 以复合物和单分子的形式结合。与游离 OPE 相比,Aβ 原纤维结合的 OPE 显示主链平面化,旋转受限,乙酯端基水合减少。这些特性与 OPE 络合作用,与已知的结合诱导 OPE 荧光开启和水溶液中猝灭、未结合状态的光谱变化的机制一致。
更新日期:2020-11-18
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