Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment

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.Author Summary: It is believed that the self association of certain protein molecules into aggregated structures, known as amyloid fibrils, plays an important role in a variety of human diseases, such as Alzheimer's disease and Parkinson's disease. Although the ability to form such amyloid fibrils is a common property for proteins, the process leading to these fibrils is incompletely understood. The early stages of the process involve small transient heterogeneous structures made of a few protein chains and are especially difficult to characterize. Here we use atomic-level simulations to explore the early part of the aggregation process for a fibril-forming fragment of the protein tau associated with Alzheimer's disease. We find that a multitude of small aggregates, rich in sheetlike structures, form through a nucleation process. Interestingly, a statistically preferred type of aggregate, consisting of two tightly packed sheets, emerges with increasing aggregate size. Growth of these larger aggregates seems to be a slow process that correlates with the emergence of more uniformly ordered sheets. We speculate that reorganization of the protein chains leading to that ordered arrangement is an important bottleneck to amyloid fibril formation for this peptide.