Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation.
Recent experiments on the kinetics of deposition and fibril elongation of the Alzheimer's beta-amyloid peptide on preexisting fibrils are analyzed. A mechanism is developed based on the dock-and-lock scheme recently proposed by Maggio and coworkers to organize their experimental observations of the kinetics of deposition of beta-peptide on preexisting amyloid fibrils and deposits. Our mechanism includes channels for (1) a one-step prion-like direct deposition on fibrils of activated monomeric peptide in solution, and (2) a two-step deposition of unactivated peptide on fibrils and subsequent reorganization of the peptide-fibril complex. In this way, the mechanism and implied "energy landscape" unify a number of schemes proposed to describe the process of fibril elongation. This beta-amyloid landscape mechanism (beta ALM) is found to be in good agreement with existing experimental data. A number of experimental tests of the mechanism are proposed. The mechanism leads to a clear definition of overall equilibrium or rate constants in terms of the energetics of the elementary underlying processes. Analysis of existing experimental data suggests that fibril elongation occurs through a two-step mechanism of nonspecific peptide absorption and reorganization. The mechanism predicts a turnover in the rate of fibril elongation as a function of temperature and denaturant concentration. Proteins 2001;42:217-229.
Massi
F
F
Department of Chemistry, Boston University, Boston, Massachusetts 02115, USA.
Straub
J E
JE
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D003432:Cross-Linking Reagents / Q000737:chemistry; D004058:Diffusion; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D011489:Protein Denaturation; D017510:Protein Folding; D012997:Solvents / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics; D014783:Viscosity
D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D010455:Peptides; D010456:Peptides, Cyclic; D012997:Solvents