Thermodynamics of beta-amyloid fibril formation

Amyloid fibers are aggregates of proteins. They are built out of a
peptide called beta-amyloid (Abeta) containing between 41 and 43
residues, produced by the action of an enzyme which cleaves a much
larger protein known as the amyloid precursor protein (APP). X-ray
diffraction experiments have shown that these fibrils are rich in
beta-structures, whereas the shape of the peptide displays an
alpha-helix structure within the APP in its biologically active
conformation. A realistic model of fibril. formation is developed based
on the 17 residues Abeta12-28 amyloid peptide, which has been shown to
form fibrils structurally similar to those of the whole A,8 peptide.
With the help of physical arguments and in keeping with experimental
findings, the Abeta12-28 monomer is assumed to be in four possible
states (i.e., native helix conformation, beta-hairpin, globular
low-energy state, and unfolded state). Making use of these monomeric
states, oligomers (dimers, tertramers, and octamers) were constructed.
With the help of short, detailed molecular dynamics calculations of the
three monomers and of a variety of oligomers, energies for these
structures were obtained. Making use of these results within the
framework of a simple yet realistic model to describe the entropic terms
associated with the variety of amyloid conformations, a phase diagram
can be calculated of the whole many-body system, leading to a
thermodynamical picture in overall agreement with the experimental
findings. In particular, the existence of micellar metastable states
seem to be a key issue to determine the thermodynamical properties of
the system. (C) 2004 American Institute of Physics.