<br>淀粉样原纤维的成核和生长,The Journal of Physical Chemistry B

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淀粉样原纤维的成核和生长
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2023-11-07 , DOI: 10.1021/acs.jpcb.3c05300
Sharareh Jalali ₁ , Ruoyao Zhang ₂ , Mikko P Haataja _{2,

3} , Cristiano L Dias ₁

Affiliation

淀粉样原纤维的形成是一种复杂的现象，在原子尺度上仍然知之甚少。在此，我们在短两亲性肽的显式溶剂中进行了扩展的无偏全原子模拟，以阐明原纤维形成的三种机制，即通过初级和次级机制的成核以及原纤维生长。我们发现初级成核是通过形成由两个彼此垂直的层压β-片层组成的中间态而发生的。随后，淀粉样原纤维脊柱从这些 β-折叠的旋转中出现，以解释彼此平行并垂直于原纤维主轴的肽。反过来，该脊柱的生长是通过对接锁定机制进行的。我们发现肽从本体溶液中或在原纤维表面扩散后停靠在原纤维尖端上。后一种对接途径显着有助于用肽填充原纤维尖端。我们还发现，侧链相互作用驱动肽在生长过程中锁定阶段的运动，使它们能够采用原纤维尖端所施加的具有原子保真度的结构。相反，当随机采样对接构象时，对接肽会陷入局部自由能最小值。我们的模拟还强调了非极性原纤维表面斑块在催化和定向小交叉β结构的形成中所发挥的作用。更广泛地说，我们的模拟为初级和次级成核以及淀粉样原纤维的生长的途径和相互作用提供了重要的新见解。

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Nucleation and Growth of Amyloid Fibrils

The formation of amyloid fibrils is a complex phenomenon that remains poorly understood at the atomic scale. Herein, we perform extended unbiased all-atom simulations in explicit solvent of a short amphipathic peptide to shed light on the three mechanisms accounting for fibril formation, namely, nucleation via primary and secondary mechanisms, and fibril growth. We find that primary nucleation takes place via the formation of an intermediate state made of two laminated β-sheets oriented perpendicular to each other. The amyloid fibril spine subsequently emerges from the rotation of these β-sheets to account for peptides that are parallel to each other and perpendicular to the main axis of the fibril. Growth of this spine, in turn, takes place via a dock-and-lock mechanism. We find that peptides dock onto the fibril tip either from bulk solution or after diffusing on the fibril surface. The latter docking pathway contributes significantly to populate the fibril tip with peptides. We also find that side chain interactions drive the motion of peptides in the lock phase during growth, enabling them to adopt the structure imposed by the fibril tip with atomic fidelity. Conversely, the docked peptide becomes trapped in a local free energy minimum when docked-conformations are sampled randomly. Our simulations also highlight the role played by nonpolar fibril surface patches in catalyzing and orienting the formation of small cross-β structures. More broadly, our simulations provide important new insights into the pathways and interactions accounting for primary and secondary nucleation as well as the growth of amyloid fibrils.

更新日期：2023-11-07

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