Open AccessMolecular Determinants of Aβ42 Adsorption to Amyloid Fibril Surfaces
Author(s) -
Mathias M. J. Bellaiche,
Robert B. Best
Publication year - 2018
Publication title -
the journal of physical chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.563
H-Index - 203
ISSN - 1948-7185
DOI - 10.1021/acs.jpclett.8b02375
Subject(s) - nucleation , fibril , adsorption , autocatalysis , molecular dynamics , chemical physics , chemistry , monomer , amyloid fibril , polar , isomerization , crystallography , biophysics , materials science , computational chemistry , amyloid β , polymer , organic chemistry , biochemistry , medicine , disease , pathology , biology , catalysis , physics , astronomy
The long lag times and subsequent rapid growth of Alzheimer's Aβ 42 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 Aβ 42 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.