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J. Biol. Chem., Vol. 280, Issue 10, 9074-9082, March 11, 2005

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Kinetics of Fibril Formation by Polyalanine Peptides^*

Hung D. Nguyen and Carol K. Hall

From the Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695-7905

Ordered -sheet complexes, termed amyloid fibrils, are the underlying structural components of the intra- and extracellular fibrillar protein deposits that are associated with a variety of human diseases, including Alzheimer's, Parkinson's, and the prion diseases. In this work, we investigated the kinetics of fibril formation using our newly developed off-lattice intermediate resolution model, PRIME. The model is simple enough to allow the treatment of large multichain systems while maintaining a fairly realistic description of protein dynamics without built-in bias toward any conformation when used in conjunction with constant temperature discontinuous molecular dynamics, a fast alternative to conventional molecular dynamics. Simulations were performed on systems containing 48–96 model Ac-KA₁₄K-NH₂ peptides. We found that fibril formation for polyalanines incorporate features that are characteristic of three models, the templated assembly, nucleated polymerization, and nucleated conformational conversion models, but that none of them gave a completely satisfactory description of the simulation kinetics. Fibril formation was nucleation-dependent, occurring after a lag time that decreased with increasing peptide concentration and increased with increasing temperature. Fibril formation appeared to be a conformational conversion process in which small amorphous aggregates -sheets ordered nucleus subsequent rapid growth of a small stable fibril or protofilament. Fibril growth in our simulations involved both -sheet elongation, in which the fibril grew by adding individual peptides to the end of each -sheet, and lateral addition, in which the fibril grew by adding already formed -sheets to its side. The initial rate of fibril formation increased with increasing concentration and decreased with increasing temperature.

Received for publication, June 30, 2004 , and in revised form, December 10, 2004.

^* This work was supported by grants from the National Institutes of Health (Grant GM-56766) and National Science Foundation (Grant CTS-9704044). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 919-515-3571; Fax: 919-515-3465; E-mail: hall{at}turbo.che.ncsu.edu.

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