Molecular Insights into the Dynamics of Amyloid Fibril Growth: Elongation and Lateral Assembly of GNNQQNY Protofibrils.

The self-assembly of peptides and proteins into ß-sheet rich amyloid fibrils is linked to both functional and pathological states. In this study, the growth of fibrillar structures of the short peptide GNNQQNY, a fragment from the yeast prion Sup35 protein, was examined. Molecular dynamics simulations were used to study alternative mechanisms of fibril growth, including elongation through binding of monomers as well as fibril self-assembly into larger, more mature structures. It was found that after binding, monomers diffused along preformed fibrils toward the ends, supporting the mechanism of fibril growth via elongation. Lateral assembly of protofibrils was found to occur readily, suggesting that this could be the key to transitioning from isolated fibrils to mature multilayer structures. Overall, the work provides mechanistic insights into the competitive pathways that govern amyloid fibril growth.

Topological properties of the energy landscape of small peptides.

In several works it has been shown that the interplay between short range and long range interactions, mimicking the hydrophobic effect, leads to the formation of the typical secondary structures in proteins, alpha-helices and beta-sheets. In this work we study in detail how the general properties of the energy landscape emerge in a model that presents both components. In this regard it proves useful a sort of perturbative approach. In our model many features of the energy landscape in absence of long range interaction can be determined analytically. The comparison between the energy landscape of this reduced model to that of the complete model gives interesting insight on the role of long range interactions.