Thermodynamics of β-amyloid fibril formation

Abstract

Amyloid fibers are aggregates of proteins. They are built out of a peptide called β-amyloid (Aβ) 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 β-structures, whereas the shape of the peptide displays an α-helix structure within the APP in its biologically active conformation. A realistic model of fibril formation is developed based on the seventeen residues Aβ12-28 amyloid peptide, which has been shown to form fibrils structurally similar to those of the whole Aβ peptide. With the help of physical arguments and in keeping with experimental findings, the Aβ12-28 monomer is assumed to be in four possible states (i.e., native helix conformation, β-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 (MD) 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.

Folding Landscapes of the Alzheimer Amyloid-β(12-28) Peptide

“…While our results agree with the previous simulations, [10][11][12] in that β-hairpins constitute a significantly populated conformational ensemble, we observe some discrepancy regarding details of the structural nature of Aβ12-28. In particular, the β-turn seen in the present work is located at positions L17V18F19F20, which represents a two residue shift along the sequence toward the N terminus with respect to the β-turn of the earlier simulations.…”

“…In particular, the β-turn seen in the present work is located at positions L17V18F19F20, which represents a two residue shift along the sequence toward the N terminus with respect to the β-turn of the earlier simulations. [10][11][12] We note that the β-hairpins sampled in these simulations were visited in our simulations (with a C α RMS∼2 Å from the most representative state †) but they were not populated significantly. In addition, the temperature-dependence of the hairpins seen here differs from that seen by the same authors, who reported a non-monotonic tem-perature-dependence.…”

“…From a theoretical perspective, the nature of the transition from the α-helical structure populated in apolar media to a β-rich structure in water was probed by Tiana and coworkers through 100 ns simulations. [10][11][12] Abbreviations used: PPII, polyproline II; SASA, solventaccessible surface area.…”

Modeling the α-helix to β-hairpin transition mechanism and the formation of oligomeric aggregates of the fibrillogenic peptide Aβ(12–28): insights from all-atom molecular dynamics simulations

“…Phys. (2004) [26]) and with several theoretical and experimental hypotheses on how monomers must be organized in the fibril (Daidone, Proteins: Structure, Function and Bioinformatics, 2004, in press).…”

“…A great deal of attention in recent literature has been devoted to the study peptide Ab(1-42), responsible for the deposition in human brains of plaques causing Alzheimer's disease, and fragmentes of Ab(1-42) which retain the ability of forming fibrils like Ab (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Molecular dynamics (MD) simulations have been used to investigate the molecular properties of selected fragments.…”