Effect of Cosolutes on the Aggregation of a Tau Fragment: A Combined Experimental and Simulation Approach.
Effect of Cosolutes on the Aggregation of a Tau Fragment: A Combined Experimental and Simulation Approach.
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共溶质对 Tau 片段聚集的影响：实验和模拟相结合的方法。
DOI：
10.1021/acs.jpcb.3c00433
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Shea,Joan-Emma
中科院分区：
文献类型：
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作者：
Arsiccio,Andrea;Liu,Xikun;Ganguly,Pritam;Buratto,StevenK;Bowers,MichaelT;Shea,Joan-Emma
本质上无序的Tau蛋白代表了阿尔茨海默病标志性的神经元缠结的主要成分。Tau的小片段，称为成对螺旋丝6（PHF 6），被认为对于原纤维的β结构核心的形成是重要的。本文采用实验和分子动力学模拟的方法研究了该片段在尿素、TMAO、蔗糖和2-羟丙基-β-环糊精（2-HPβCD）等共溶质存在下的聚集行为。使用一种新的隐式溶剂化方法（MIST -隐式溶剂化热力学模型），其中基于转移自由能概念的能量贡献描述了共溶质的效果。模拟预测相比，硫磺素-T和原子力显微镜的结果，观察到的良好的一致性证实了本文提出的计算方法的预测能力。模拟和实验均表明，尿素和2-HPβCD抑制了PHF 6的聚集，而TMAO和蔗糖则稳定了相关构象。HPβCD抑制聚集的显著能力代表了未来应用的极有前景的结果，特别是考虑到该分子作为脑药物载体和药物制剂中增溶剂/赋形剂的广泛使用。
The intrinsically disordered protein Tau represents the main component of neurofibrillary tangles that are a hallmark of Alzheimer’s disease. A small fragment of Tau, known as paired helical filament 6 (PHF6), is considered to be important for the formation of the β-structure core of the fibrils. Here we study the aggregation of this fragment in the presence of different cosolutes, including urea, TMAO, sucrose and 2-hydroxypropyl-β-cyclodextrin (2-HPβCD), using both experiments and molecular dynamics simulations. A novel implicit solvation approach (MIST - Model with Implicit Solvation Thermodynamics) is used, where an energetic contribution based on the concept of transfer free energies describes the effect of the cosolutes. The simulation predictions are compared to thioflavin-T and atomic force microscopy results, and the good agreement observed confirms the predictive ability of the computational approach herein proposed. Both simulations and experiments indicate that PHF6 aggregation is inhibited in the presence of urea and 2-HPβCD, while TMAO and sucrose stabilize associated conformations. The remarkable ability of HPβCD to inhibit aggregation represents an extremely promising result for future applications, especially considering the widespread use of this molecule as a drug carrier to the brain and as a solubilizer/excipient in pharmaceutical formulations.