GNNQQNY—Investigation of Early Steps during Amyloid Formation

• Published in: Biophysical journal Vol. 98; no. 6; pp. 1038 - 1045
• Main Authors: Reddy, Allam S., Chopra, Manan, de Pablo, Juan J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-03-2010; Biophysical Society; The Biophysical Society
• Subjects: Amyloid - chemistry; Amyloid - ultrastructure; Biophysics; Computer Simulation; Models, Chemical; Models, Molecular; Neurological disorders; Pathology; Peptides; Peptides - chemistry; Protein; Protein Conformation; Proteins; Statistical analysis
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2009.10.057

Protein aggregation has been implicated in the pathology of several neurodegenerative diseases, and a better understanding of how it proceeds is essential for the development of therapeutic strategies. Recently, the amyloidogenic heptapeptide GNNQQNY has emerged as a molecule of choice for fundamental studies of protein aggregation. A number of experimental and computational studies have examined the structure of the GNNQQNY aggregate. Less work, however, has been aimed at understanding its aggregation pathway. In this study, we present a detailed computational analysis of such a pathway. To that end, transition path sampling Monte Carlo simulations are used to examine the dimerization process. A statistical analysis of the reaction pathways shows that the dimerization reaction proceeds via a zipping mechanism, initiated with the formation of distinct contacts at the third residue (
N). Asparagine residues are found to play a key role in the early stages of aggregation. And, contrary to previous belief, it is also shown that the tyrosine terminal group is not required to stabilize the dimer. In fact, an asparagine residue leads to faster aggregation of the peptide.