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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.

Abeta40, the 40-residue form of Amyloid beta, is an intrinsically disordered protein which is involved in Alzheimer's disease and prone to form fibrils.We explored its conformational landscape by atomistic simulations in explicit solvent and NMR-guided metadynamics, an enhanced sampling technique based on the experimental chemical shifts data that allows predicting the relative free energy of the different states involved in the folding process of a protein.This approach provides a picture in striking consistency with experimental NMR measurements, with the global free energy minimum consisting of non-compact and disordered structures.However, the free energy landscape includes also a large amount of partially folded conformations with a relative high secondary structure content and a free energy only 3 kcal/mol higher than the disordered minimum. This structural characterization of Abeta40 provides a library of possible metastable states which can be involved in the aggregation process and used as targets for docking studies to design inhibitors to bind the Abeta fragments in order to prevent their fibrillation.

Starting from a disordered aggregate, we have simulated the formation of ordered amyloid-like beta structures in a system formed by 18 poly-valine chains in explicit solvent, by 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 anti-parallel 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 anti-parallel beta-sheets, 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 towards 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.

By extended atomistic simulations in explicit solvent and bias-exchange metadynamics, we study the aggregation process of 18 chains of the C-terminal segment of amyloid-beta, an intrinsically disordered protein involved in Alzheimer's disease and prone to form fibrils. Starting from a disordered aggregate, we are able to observe the formation of an ordered nucleus rich in beta sheets. The rate limiting step in the nucleation pathway involves crossing a barrier of approximately 40 kcal/mol and is associated with the formation of a very specific interdigitation of the side chains belonging to different sheets. This structural pattern is different from the one observed experimentally in a microcrystal of the same system, indicating that the structure of a "nascent'' fibril may differ from the one of an "extended'' fibril. DOI: 10.1103/PhysRevLett.110.168103