Oxidatively-mediated in silico epimerization of a highly amyloidogenic segment in the human calcitonin hormone (hCT15-19) |
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| Institution: | 1. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada;2. School of Physics and Astronomy, Queen Mary University of London, 327 Mile End Road, London, E1 4NS, United Kingdom;3. Department of Biochemistry, Faculty of Medicine, University of Toronto, 1 King''s College Cir, Toronto, ON, M5S 1A8, Canada;4. Department of Molecular Medicine, Hospital for Sick Children, 1 King''s College Cir, Toronto, ON, M5S 1A8, Canada;5. Department of Chemistry, Faculty of Arts & Science, University of Toronto, 80 St George St, Toronto, ON, M5S 3H6, Canada;6. Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada;7. Department of Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany;8. CEITEC – Central European Institute of Technology, Masaryk University, 625 00 Brno, Czech Republic;9. Institute of Food Engineering, Faculty of Engineering, University of Szeged, H-6724 Szeged, Mars tér 7, Hungary;10. Institue of Chemistry, Faculty of Materials Science and Engineering, University of Miskolc, H-3515 Miskolc, Hungary;11. Ferenc Rákóczi II. Transcarpathian Hungarian Institute, Beregszász, Transcarpathia, 90200, Ukraine;1. Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan;2. Bioorganic Research Institute, Suntory Foundation for Life Sciences, 8-1-1, Seikadai, Seika-cho, Soraku-gun, Kyoto 619-0284, Japan;3. Frontier Science Research Center, University of Miyazaki, Miyazaki, Miyazaki 889-1692, Japan;4. National Institute for Basic Biology, Laboratory of Morphogenesis, 38 Nishigonaka Myodaiji, Okazaki 444-8585, Japan;5. Institute of Noto SATOUMI Education and Studies, Noto-cho, Ishikawa 927-0553, Japan;6. Department of Animal Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan;7. Department of Marine Biosciences, Division of Marine Science, Tokyo University of Marine Science and Technology, Minato-ku, Tokyo 108-8477, Japan;8. Department of Biology, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Ichikawa, Chiba 272-0827, Japan;9. Department of Zoology, D.D.U. Gorakhpur University, Gorakhpur 273-009, India;1. Institute for Oral Science, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan;2. Department of Oral Biochemistry, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan;3. Japan Osteoporosis Foundation, 11-2 Nihonbashi-kobunacho, Chuo-ku, Tokyo 103-0024, Japan;4. Noto Marine Laboratory, Institute of Nature and Environment Technology, Kanazawa University, 4-1 Ogi, Noto-cho, Ishikawa 927-0553, Japan;5. Institute of Nature Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;1. Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, People''s Republic of China;2. Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX, 77030, United States |
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| Abstract: | 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. |
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| Keywords: | DFNKF Amyloidosis Aggregation Oxidative-stress Molecular ageing Peptide |
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