Kinetics of fibril formation by polyalanine peptides - Aggregation & Cleavage

Kinetics of fibril formation by polyalanine peptides
Engineering Village 2
? 2006 Elsevier Inc
Accession number: 05149022959

Title: Kinetics of fibril formation by polyalanine peptides

Authors: Nguyen, Hung D.; Hall, Carol K.

Author affiliation: Dept. of Chem. and Biomol. Eng., North Carolina State University, Raleigh, NC 27695-7905, United States

Serial title: Journal of Biological Chemistry

Abbreviated serial title: J. Biol. Chem.

Volume: v 280

Issue: n 10

Issue date: Mar 11 2005

Publication year: 2005

Pages: p 9074-9082

Language: English

ISSN: 0021-9258

CODEN: JBCHA3

Document type: Journal article (JA)

Publisher: American Society for Biochemistry and Molecular Biology Inc., Bethesda, MD 20814, United States

Abstract: 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. ? 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Number of references: 82

Ei main heading: Aromatic polymers

Ei controlled terms: Proteins - Diseases - Conformations - Molecular dynamics - Polymerization - Nucleation - Mathematical models - Computer simulation

Uncontrolled terms: Fibril formation - Polyalanine peptides - Human diseases - Nucleated polymerization

Ei classification codes: 815.1.1 Organic Polymers - 804.1 Organic Compounds - 461.6 Medicine - 801.4 Physical Chemistry - 815.2 Polymerization - 933.1.2 Crystal Growth - 921 Applied Mathematics - 723.5 Computer Applications

Treatment: Theoretical (THR)

DOI: 10.1074/jbc.M407338200

Database: Compendex

Compilation and indexing terms, ? 2006 Elsevier Inc. All rights reserved
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