Zhang Ruoyao, Jalali Sharareh, Dias Cristiano Luis, Haataja Mikko P
Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544, USA.
Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102, USA.
PNAS Nexus. 2024 Feb 1;3(2):pgae045. doi: 10.1093/pnasnexus/pgae045. eCollection 2024 Feb.
Amyloid fibrils have long been associated with many neurodegenerative diseases. The conventional picture of the formation and proliferation of fibrils from unfolded proteins comprises primary and secondary nucleation of oligomers followed by elongation and fragmentation thereof. In this work, we first employ extensive all-atom molecular dynamics (MD) simulations of short peptides to investigate the governing processes of fibril growth at the molecular scale. We observe that the peptides in the bulk solution can bind onto and subsequently diffuse along the fibril surface, which leads to fibril elongation via either bulk- or surface-mediated docking mechanisms. Then, to guide the quantitative interpretation of these observations and to provide a more comprehensive picture of the growth kinetics of single fibrils, a continuum model which incorporates the key processes observed in the MD simulations is formulated. The model is employed to investigate how relevant physical parameters affect the kinetics of fibril growth and identify distinct growth regimes. In particular, it is shown that fibrils which strongly bind peptides may undergo a transient exponential growth phase in which the entire fibril surface effectively acts as a sink for peptides. We also demonstrate how the relevant model parameters can be estimated from the MD trajectories. Our results provide compelling evidence that the overall fibril growth rates are determined by both bulk and surface peptide fluxes, thereby contributing to a more fundamental understanding of the growth kinetics of amyloid-like fibrils.
淀粉样纤维长期以来一直与许多神经退行性疾病相关。从未折叠蛋白形成和增殖纤维的传统图景包括寡聚体的初级和次级成核，随后是其伸长和断裂。在这项工作中，我们首先对短肽进行广泛的全原子分子动力学（MD）模拟，以研究分子尺度上纤维生长的主导过程。我们观察到，本体溶液中的肽可以结合到纤维表面并随后沿其扩散，这通过本体或表面介导的对接机制导致纤维伸长。然后，为了指导对这些观察结果的定量解释，并提供单个纤维生长动力学的更全面图景，我们制定了一个包含MD模拟中观察到的关键过程的连续介质模型。该模型用于研究相关物理参数如何影响纤维生长动力学，并确定不同的生长模式。特别是，结果表明，强烈结合肽的纤维可能会经历一个短暂的指数生长阶段，其中整个纤维表面有效地充当肽的汇。我们还展示了如何从MD轨迹估计相关模型参数。我们的结果提供了令人信服的证据，表明纤维的总体生长速率由本体和表面肽通量共同决定，从而有助于更深入地理解淀粉样纤维的生长动力学。
