title: Multidimensional view of amyloid fibril nucleation in atomistic detail.
abstract: 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.
authors.affiliation: SISSA , Via Bonomea 265, Trieste, Italy.
authors.forename: Fahimeh
authors.initials: F
authors.lastname: Baftizadeh
authors.forename: Xevi
authors.initials: X
authors.lastname: Biarnes
authors.forename: Fabio
authors.initials: F
authors.lastname: Pietrucci
authors.forename: Fabio
authors.initials: F
authors.lastname: Affinito
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laio
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000682:Amyloid