Baftizadeh, Fahimeh Biarnes, Xevi Pietrucci, Fabio Affinito, Fabio Laio, Alessandro Multidimensional View of Amyloid Fibril Nucleation in Atomistic Detail Starting from a disordered aggregate, we have simulated the formation of ordered amyloid-like beta structures in a system formed by 18 polyvaline chains in explicit solvent, employing molecular dynamics accelerated by bias-exchange metadynamics. We exploited 8 different collective variables to compute the free energy of hundreds of putative aggregate structures, with variable content of parallel and antiparallel β-sheets and different packing among the sheets. This allowed characterizing in detail a possible nucleation pathway for the formation of amyloid fibrils: first the system forms a relatively large ordered nucleus of antiparallel β-sheets, and then a few parallel sheets start appearing. The relevant nucleation process culminates at this point: when a sufficient number of parallel sheets is formed, the free energy starts to decrease toward a new minimum in which this structure is predominant. The complex nucleation pathway we found cannot be described within classical nucleation theory, namely employing a unique simple reaction coordinate like the total content of β-sheets. Amyloid Fibril Nucleation;18 polyvaline chains;nucleation pathway 2012-02-29
    https://acs.figshare.com/articles/journal_contribution/Multidimensional_View_of_Amyloid_Fibril_Nucleation_in_Atomistic_Detail/2545888
10.1021/ja210826a.s001