Chemistry
Formation and growth of oligomers: A monte carlo study of an amyloid tau fragment
Document Type
Article
Abstract
Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are β-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the β-sheets. The larger aggregates seen in our simulations are all composed of two twisted β-sheets, packed against each other with hydrophobic side chains at the sheet-sheet interface. These β-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel β-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel β-sheet structure increases with aggregate size. We speculate that the reorganization of the β-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils. © 2008 Li et al.
Publication Title
PLoS Computational Biology
Publication Date
1-2008
Volume
4
Issue
12
ISSN
1553-734X
DOI
10.1371/journal.pcbi.1000238
Repository Citation
Li, Da Wei; Mohanty, Sandipan; Irbäck, Anders; and Huo, Shuanghong, "Formation and growth of oligomers: A monte carlo study of an amyloid tau fragment" (2008). Chemistry. 102.
https://commons.clarku.edu/chemistry/102
Cross Post Location
Student Publications