Frigori Rafael B, Barroso da Silva Fernando L, Carvalho Patrícia P D, Alves Nelson A
Universidade Tecnológica Federal do Paraná, Rua Cristo Rei 19, Toledo 85902-490, Paraná, Brazil.
Departamento de Ciências Biomoleculares, FCFRP, Universidade de São Paulo, Avenida do Café, s/no, Ribeirão Preto 14040-903, São Paulo, Brazil.
J Phys Chem B. 2020 Apr 9;124(14):2798-2805. doi: 10.1021/acs.jpcb.0c01360. Epub 2020 Mar 31.
We investigate the prevalence, and so the role in the amyloidogenesis, of biased conformations in large ensembles of monomeric forms for Aβ42 and Aβ40 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 Aβ 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.
我们研究了Aβ42和Aβ40单体形式的大集合中偏向构象的患病率及其在淀粉样蛋白生成中的作用，这些偏向构象可触发由对接-锁定机制描述的原纤维的形成和生长。我们将这些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，在由具有精确力场的分子动力学在明确溶剂化条件下生成的Aβ肽统计构象集合中搜索相似结构，通过与剩余偶极耦合（RDC）实验的比较揭示了其高质量。这些内在无序肽生成的构象集合不包含与淀粉样生成模板高度相似的构象。这是模板样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，通过合适的pH条件可以提高这种稳定性，这有助于触发原纤维的伸长。此外，我们对自由能景观、氢键发生率和主成分分析分布的分析强调了多体远程协同相互作用的相关性，这些相互作用可能作用于罕见的预先存在的结构偏向构象，以解释原纤维的出现。
