Mapping the configurational landscape and aggregation phase behavior of the tau protein fragment PHF6
Mapping the configurational landscape and aggregation phase behavior of the tau protein fragment PHF6
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DOI：
10.1073/pnas.2309995120
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发表时间：
2023-11
影响因子：
11.1
通讯作者：
Evan Pretti;M. S. Shell
中科院分区：
文献类型：
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作者：
Evan Pretti;M. S. Shell
微管相关蛋白tau的淀粉样蛋白聚集是阿尔茨海默病和其他tau蛋白病病理学的核心，但tau蛋白纤维化的分子细节知之甚少。PHF 6六肽形成在所有病理性tau结构中发现的交叉β棘的关键部分。在这里，我们表明，一个完全预测，自下而上的粗粒度模型PHF6阐明了层次结构和驱动力的聚合。大规模的模拟量化的相行为，纤维化热力学，和低聚物的构象景观PHF6，纤维成核和生长的基本因素，并进一步提供辅因子诱导的聚集机制。这些见解表明，现代多尺度方法的潜力，预测性地通知实验工作，研究tau片段与详细的分子图片的聚集。
Significance Amyloid aggregation of the microtubule-associated protein tau is central to the pathology of Alzheimer’s disease and other tauopathies, but the molecular details underlying tau fibrillization are poorly understood. The PHF6 hexapeptide forms a crucial part of the cross-β spines found in all pathological tau structures. Here, we show that an entirely predictive, bottom-up coarse-grained model of PHF6 illuminates the hierarchy of structures and driving forces underlying its aggregation. Large-scale simulations quantify the phase behavior, fibrillization thermodynamics, and oligomer conformational landscape of PHF6, essential factors underlying fibril nucleation and growth, and further offer mechanisms of cofactor-induced aggregation. These insights suggest the potential for modern multiscale methods to predictively inform experimental efforts to studytau fragments with detailed molecular pictures of aggregation.