Thermodynamics of beta-amyloid fibril formation

Amyloid fibers are aggregates of proteins. They are built out of a peptide called b-amyloid ~Ab!
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 b-structures, whereas the shape of the peptide displays an a-helix
structure within the APP in its biologically active conformation. A realistic model of fibril formation
is developed based on the 17 residues Ab12-28 amyloid peptide, which has been shown to form
fibrils structurally similar to those of the whole Ab peptide.With the help of physical arguments and
in keeping with experimental findings, the Ab12-28 monomer is assumed to be in four possible
states ~i.e., native helix conformation, b-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.