MOLECULAR SIMULATION OF THE AMYLOID BETA-PEPTIDE A-BETA-(1-40) OF ALZHEIMERS-DISEASE

The amyloid A beta(1-40) peptide of Alzheimer's disease was chosen as model compound. This A beta peptide is an intrinsically soluble peptid e; the C-terminal amino acids are less hydrophilic than the amino acid s at the N-terminus, and the degree of hydrophilicity of the N-terminu s depends strongly on the pH. The stronger local energy minimum of the random coil and a-helix means that the two conformations are more sta ble in solution. The relatively high-energy domain of the beta-sheet a llows to surmount better the energy-barrier height during the formatio n of an activated complex with polarized ligands and macromolecules. I t appears that interactions around the Phe19 and Phe20 area (hydrophob ic core) of paired beta-sheets play a key role in formatting chi-like filaments. Energy calculation of a bi-and trimer supports the view tha t the aggregates are energetically stable oligomers which can easily b e denatured, however. A perspective in drug research is to develop com pounds that stabilize specifically the alpha-helix and random conforma tions of A beta(1-40), or inhibit the hydrophobic core.