Nguyen Phuong H, Derreumaux Philippe
CNRS, Université Paris Cité, UPR 9080, Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, 13 Rue Pierre et Marie Curie, 75005 Paris, France.
Institut Universitaire de France (IUF), 75005 Paris, France.
J Phys Chem B. 2022 May 12;126(18):3431-3438. doi: 10.1021/acs.jpcb.2c01692. Epub 2022 Apr 27.
The aggregation of the tau protein plays a significant role in Alzheimer's disease, and the tau R3-R4 domain spanning residues 306-378 was shown to form the amyloid fibril core of a full-length tau. The conformations of the tau R3-R4 monomer in the bulk solution and at the surface of membranes are unknown. In this study, we address these questions by means of atomistic molecular dynamics. The simulations in the bulk solution show a very heterogeneous ensemble of conformations with low β and helical contents. The tau R3-R4 monomer has the propensity to form transient β-hairpins within the R3 repeat and between the R3 and R4 repeats and parallel β-sheets spanning the R3 and R4 repeats. The simulations also show that the surface of the membrane does not induce β-sheet insertion and leads to an ensemble of structures very different from those in the bulk solution. They also reveal the dynamical properties of the membrane-bound state of the tau R3-R4 monomer, enabling insertion of the residues 306-318 and 376-378.
tau蛋白的聚集在阿尔茨海默病中起着重要作用，并且已表明跨越306 - 378位残基的tau R3 - R4结构域形成了全长tau的淀粉样原纤维核心。tau R3 - R4单体在本体溶液和膜表面的构象尚不清楚。在本研究中，我们通过原子分子动力学来解决这些问题。本体溶液中的模拟显示出构象非常不均一的集合，β和螺旋含量较低。tau R3 - R4单体倾向于在R3重复序列内以及R3和R4重复序列之间形成瞬时β - 发夹结构，以及跨越R3和R4重复序列的平行β - 折叠。模拟还表明，膜表面不会诱导β - 折叠插入，并且导致了与本体溶液中结构非常不同的结构集合。它们还揭示了tau R3 - R4单体膜结合状态的动力学特性，使得306 - 318位和376 - 378位残基能够插入。
