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Energy landscape theory for Alzheimer's amyloid β‐peptide fibril elongation
Author(s) -
Massi Francesca,
Straub John E.
Publication year - 2000
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/1097-0134(20010201)42:2<217::aid-prot90>3.0.co;2-n
Subject(s) - fibril , energy landscape , elongation , amyloid fibril , peptide , amyloid (mycology) , biophysics , amyloid β , chemistry , neuroscience , biochemistry , materials science , medicine , biology , pathology , disease , ultimate tensile strength , inorganic chemistry , metallurgy
Recent experiments on the kinetics of deposition and fibril elongation of the Alzheimer's β‐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 β‐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 β‐amyloid landscape mechanism (βALM) 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. © 2000 Wiley‐Liss, Inc.