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J Phys Chem Lett. 2018 Nov 15;9(22):6437-6443. doi: 10.1021/acs.jpclett.8b02375. Epub 2018 Oct 29.

Molecular Determinants of Aβ42 Adsorption to Amyloid Fibril Surfaces.

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Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases , National Institutes of Health , Bethesda , Maryland 20892-0520 , United States.
Department of Chemistry , University of Cambridge , Lensfield Road, Cambridge CB2 1EW , United Kingdom.


The long lag times and subsequent rapid growth of Alzheimer's Aβ42 fibrils can be explained by a secondary nucleation step, in which existing fibril surfaces are able to nucleate the formation of new fibrils via an autocatalytic process. The molecular mechanism of secondary nucleation, however, is still unknown. Here we investigate the first step, namely, adsorption of the Aβ42 peptide monomers onto the fibril surface. Using long all-atom molecular simulations and an enhanced sampling scheme, we are able to generate a diverse ensemble of binding events. The resulting thermodynamics of adsorption are consistent with experiment as well as with the requirements for effective autocatalysis determined from coarse-grained simulations. We identify the key interactions stabilizing the adsorbed state, which are predominantly polar in nature, and relate them to the effects of known disease-causing mutations.

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