Molecular Simulation of the Amyloid β-Peptide Aβ-(1-40) of Alzheimer's Disease

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Abstract
The amyloid Aβ(1–40) peptide of Alzheimer's disease was chosen as model compound. This Aβ peptide is an intrinsically soluble peptide; the C-terminal amino acids are less hydrophilic than the amino acids at the N-terminus, and the degree of hydrophilicity of the N-terminus depends strongly on the pH. The stronger local energy minimum of the random coil and α-helix means that the two conformations are more stable in solution. The relatively high-energy domain of the β-sheet allows to surmount better the energy-barrier height during the formation of an activated complex with polarized ligands and macromolecules. It appears that interactions around the Phe19 and Phe20 area (hydrophobic core) of paired β-sheets play a key role in formatting χ-like filaments. Energy calculation of a bi- and trimer supports the view that the aggregates are energetically stable oligomers which can easily be denatured, however. A perspective in drug research is to develop compounds that stabilize specifically the α-helix and random conformations of Aβ(1–40), or inhibit the hydrophobic core.

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