Occurrence of Biased Conformations as Precursors of Assembly States in Fibril Elongation of Amyloid-β Fibril Variants: An In Silico Study
Occurrence of Biased Conformations as Precursors of Assembly States in Fibril Elongation of Amyloid-β Fibril Variants: An In Silico Study
复制标题
DOI：
10.1021/acs.jpcb.0c01360
复制
发表时间：
2020-04-09
影响因子：
3.3
通讯作者：
Alves, Nelson A.
中科院分区：
文献类型：
--
作者：
Frigori, Rafael B.;Barroso da Silva, Fernando L.;Alves, Nelson A.
我们研究了 A eta 42 和 A beta 40 单体形式大集合中偏向构象的普遍性以及在淀粉样蛋白生成中的作用，这些构象可以触发由停靠锁机制描述的原纤维的形成和生长。我们将这种偏向构象建模为构成蛋白质数据库原纤维 2beg、2mxu 和 2lmn 的结构单体单元。这些单元被用作模板，在通过分子动力学生成的 A β 肽的统计构象集合中搜索相似的结构，并在显式溶剂化中具有精确的力场，通过与残余偶极耦合 (RDC) 实验的比较揭示了其高质量。这些本质上无序的肽产生的构象集合不包含与淀粉样蛋白形成模板高度相似的构象。这是类模板构象表现出的低热力学稳定性的结果。进一步的恒定 pH 蒙特卡罗研究表明，适当的 pH 条件可以提高这种稳定性，这有助于触发原纤维伸长。此外，我们对自由能景观、氢键普遍性和主成分分析分布的分析强调了多体远程合作相互作用的相关性，可能作用于不常见的预先存在的结构偏向构象，以解释原纤维的出现。
We investigate the prevalence, and so the role in the amyloidogenesis, of biased conformations in large ensembles of monomeric forms for A eta 42 and A beta 40 that can trigger the formation and growth of fibrils described by a dock-lock mechanism. We model such biased conformations as the structural monomeric units that constitute the Protein Data Bank fibrils 2beg, 2mxu, and 2lmn. These units were employed as templates to search for similar structures in statistical conformational ensembles of A beta peptides generated by molecular dynamics with an accurate force field in explicit solvation, whose high quality is revealed by comparison with residual dipolar coupling (RDC) experiments. The conformational ensembles generated by these intrinsically disordered peptides do not contain conformations highly similar to the amyloidogenic templates. This is a consequence of the low thermodynamic stability exhibited by the template-like conformations. A further constant-pH Monte Carlo study has revealed that this stability can be increased by suitable pH conditions, which helps to trigger the fibril elongation. Moreover, our analyses on the free energy landscapes, hydrogen bond prevalences, and principal component analysis distributions emphasize the relevance of many-body long-range cooperative interactions, likely acting over the infrequent preexisting structurally biased conformations, to explain the fibrils' emergence.