Grasso Gianvito, Deriu Marco A, Tuszynski Jack A, Gallo Diego, Morbiducci Umberto, Danani Andrea
Istituto Dalle Molle Di Studi Sull'intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale Della Svizzera Italiana (SUPSI), Università Della Svizzera Italiana (USI), Centro Galleria 2, Manno, 6928, Switzerland.
Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
Proteins. 2016 Jan;84(1):52-9. doi: 10.1002/prot.24954. Epub 2015 Nov 23.
In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.
在本文中，我们报告了脊髓小脑共济失调蛋白1（Ataxin-1）的AXH单体的分子动力学模拟结果。AXH结构域在Ataxin-1聚集过程中起着关键作用，而Ataxin-1聚集伴随着1型脊髓小脑共济失调的发生和发展。我们的模拟涉及经典分子动力学和副本交换分子动力学，随后对所得轨迹进行主成分分析，结果表明蛋白质结构存在显著的构象波动，尤其是在N端区域。我们发现这些波动可由热噪声产生，因为构象之间的自由能垒足够小，能够发生热激发跃迁。与先前的实验结果一致，我们的结果可作为未来设计Ataxin聚集抑制剂的基础，这些抑制剂需要将本研究中确定的几个关键构象作为配体结合的分子靶点。
