Regular Article - Computational Methods
Exploring the locking stage of NFGAILS amyloid fibrillation via transition manifold analysis
Department of Mathematics, Freie Universität Berlin, Berlin, Germany
2 Department of Chemistry, Freie Universität Berlin, Berlin, Germany
3 Department of Physics, Freie Universität Berlin, Berlin, Germany
4 Zuse Institute Berlin, Berlin, Germany
Accepted: 7 September 2021
Published online: 30 September 2021
We demonstrate the application of the transition manifold framework to the late-stage fibrillation process of the NFGAILS peptide, a amyloidogenic fragment of the human islet amyloid polypeptide (hIAPP). This framework formulates machine learning methods for the analysis of multi-scale stochastic systems from short, massively parallel molecular dynamical simulations. We identify key intermediate states and dominant pathways of the process. Furthermore, we identify the optimally timescale-preserving reaction coordinate for the dock-lock process to a fixed pre-formed fibril and show that it exhibits strong correlation with the mean native hydrogen-bond distance. These results pave the way for a comprehensive model reduction and multi-scale analysis of amyloid fibrillation processes.
© The Author(s) 2021
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