Nucleation and Growth of Amyloid Fibrils

纤维 成核 淀粉样纤维 化学 化学物理 结晶学 分子动力学 生物物理学 垂直的 对接(动物) 淀粉样β 计算化学 生物化学 医学 几何学 疾病 有机化学 数学 病理 护理部 生物
作者
Sharareh Jalali,Ruoyao Zhang,Mikko Haataja,Cristiano L. Dias
出处
期刊:Journal of Physical Chemistry B [American Chemical Society]
卷期号:127 (45): 9759-9770 被引量:7
标识
DOI:10.1021/acs.jpcb.3c05300
摘要

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.
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