Multidimensional view of amyloid fibril nucleation in atomistic detail

Fahimeh Baftizadeh, Xevi Biarnes, Fabio Pietrucci, Fabio Affinito, Alessandro Laio

Producció científica: Article en revista indexadaArticleAvaluat per experts

75 Cites (Scopus)


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.

Idioma originalAnglès
Pàgines (de-a)3886-3894
Nombre de pàgines9
RevistaJournal of the American Chemical Society
Estat de la publicacióPublicada - 29 de febr. 2012


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