Computational simulations of the early steps of protein aggregation

Abstract

There is strong evidence that the oligomers of key proteins, formed during the early steps of aggregation, could be the primary toxic species associated with human neuro-degenerative diseases, such as Alzheimer's and prion diseases. Here, we review recent progress in the development of computational approaches in order to understand the structures, dynamics and free energy surfaces of oligomers. We also discuss possible research directions for the coming years.

Figure 1

Free energy surface of Aβ(16–22) dimer at 310 K obtained from REMD-OPEP simulation. The two reaction coordinates used are the cosine of the angle between the two chains and the extended status of the two chains. The structures A–H of low free energy (in kcal/mol) are shown.

Figure 2

A generic aggregation picture derived from ART- and MD-OPEP simulations. Starting from a randomly chosen state, the peptides form amorphous aggregates. From there, the outcome changes with the oligomer size (OS) and chain length (L). For OS < 9 and L < 8, rapid aggregation proceeds directly to ordered β-sheets or indirectly through β-barrels. The double arrows indicate reversibility. For larger OS or L, aggregation into β-barrels and ordered β-sheets is very slow and rare.