New Insight into Amyloid-β Fibril Growth and its Inhibition: Kinetic Network Analysis of Multi-Scale Molecular Dynamics Simulations

Abstract

Formation of amyloid fibrils by amyloid-β peptides (Aβ) in patient brains is a hallmark of Alzheimer's disease. A major step of Aβ fibril formation is elongation of fibrils by unstructured Aβ peptides, involving Aβ binding and structural transitions. The atomic detail of the structural transitions remains poorly understood. Computational characterization of the structural transitions is limited owing to the long timescale of Aβ fibril elongation. We present here our recent effort in overcoming the computational timescale limit by applying a novel computational approach combining a multi-scale model, enhanced sampling techniques and kinetic network analysis to tackle Aβ fibril elongation [1]. In the framework of this efficient approach, we are able to perform simulations reaching the millisecond timescale and determine in a systematic way detailed transition pathways and kinetics for Aβ fibril elongation. The resulting kinetic model of fibril elongation does not only reveal an atomic picture of pathways of Aβ fibril elongation not seen before, involving special structures of Aβ monomers as important kinetic intermediates, but does explain also a puzzling experimental observation, namely unidirectional growth of Aβ fibrils. Moreover, the kinetic model reveals possible kinetic and thermodynamic effects of ligand binding on fibril growth, providing new insights into inhibitor design.Reference:[1] Han, W.; Schulten, K. J. Am. Chem. Soc. 2014, 136, 12450.