Baftizadeh, FahimehBiarnes, XeviPietrucci, FabioAffinito, FabioLaio, Alessandro2012-04-052012-04-052012-04-05201210.1021/ja210826ahttps://infoscience.epfl.ch/handle/20.500.14299/79201WOS:000301161600043Starting 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.Molecular-Dynamics SimulationsMonte-Carlo SimulationsProtein AggregationForce-FieldsPeptideOligomersMechanismA-Beta(16-22)EnsembleConformationstext::journal::journal article::research article