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 beta-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 beta-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 beta-sheets. © 2012 American Chemical Society.
|Titolo:||Multidimensional View of Amyloid Fibril Nucleation in Atomistic Detail|
|Autori:||Baftizadeh, F; Biarnes, X; Pietrucci, F; Affinito, F; Laio, A|
|Rivista:||JOURNAL OF THE AMERICAN CHEMICAL SOCIETY|
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||10.1021/ja210826a|
|Appare nelle tipologie:||1.1 Journal article|