In order to study the effects of peptide exposure to oxidative attack, we chose a model reaction in which the hydroxyl radical discretely abstracts a hydrogen atom from the α-carbon of each residue of a highly amyloidogenic region in the human calcitonin hormone, hCT15-19. Based on a combined Molecular Mechanics / Quantum Mechanics approach, the extended and folded L- and D-configuration and radical intermediate hCT15-19 peptides were optimized to obtain their compactness, secondary structure and relative thermodynamic data. The results suggest that the epimerization of residues is generally an exergonic process that can explain the cumulative nature of molecular aging. Moreover, the configurational inversion induced conformational changes can cause protein dysfunction. The epimerization of the central residue to the D-configuration induced a hairpin structure in hCT15-19, concomitant with a possible oligomerization of human calcitonin into Aβ(1-42)-like amyloid fibrils present in patients suffering from Alzheimer's disease.

Department of Biochemistry Faculty of Medicine University of Toronto 1 King's College Cir Toronto ON M5S 1A8 Canada; Department of Molecular Medicine Hospital for Sick Children 1 King's College Cir Toronto ON M5S 1A8 Canada

Department of Chemistry Faculty of Arts and Science University of Toronto 80 St George St Toronto ON M5S 3H6 Canada; Department of Chemistry York University 4700 Keele Street Toronto ON M3J 1P3 Canada

Department of Chemistry Faculty of Arts and Science University of Toronto 80 St George St Toronto ON M5S 3H6 Canada; Institue of Chemistry Faculty of Materials Science and Engineering University of Miskolc H 3515 Miskolc Hungary

Department of Physiology Faculty of Medicine University of Toronto 1 King's College Circle Toronto Ontario M5S 1A8 Canada

Department of Structural Biochemistry Forschungszentrum Jülich 52425 Jülich Germany; CEITEC Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic

Institue of Chemistry Faculty of Materials Science and Engineering University of Miskolc H 3515 Miskolc Hungary

Institue of Chemistry Faculty of Materials Science and Engineering University of Miskolc H 3515 Miskolc Hungary; Ferenc Rákóczi 2 Transcarpathian Hungarian Institute Beregszász Transcarpathia 90200 Ukraine

Institute of Food Engineering Faculty of Engineering University of Szeged H 6724 Szeged Mars tér 7 Hungary

School of Physics and Astronomy Queen Mary University of London 327 Mile End Road London E1 4NS United Kingdom

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