Oxidatively-mediated in silico epimerization of a highly amyloidogenic segment in the human calcitonin hormone (hCT 15-19 )

Ahmad Kamal M. Hamid, Joanna C. Salvatore, Ke Wang, Prashantha Murahari, Andrea Guljas, Anita Rágyanszki, Michael Owen, Balázs Jójárt, Milán Szőri, Imre G. Csizmadia, Béla Viskolcz, Béla Fiser

Research output: Article

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, hCT 15-19 . Based on a combined Molecular Mechanics / Quantum Mechanics approach, the extended and folded L- and D-configuration and radical intermediate hCT 15-19 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 hCT 15-19 , concomitant with a possible oligomerization of human calcitonin into Aβ(1–42)-like amyloid fibrils present in patients suffering from Alzheimer's disease.

Original languageEnglish
Pages (from-to)259-269
Number of pages11
JournalComputational Biology and Chemistry
Volume80
DOIs
Publication statusPublished - jún. 2019

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Organic Chemistry
  • Computational Mathematics

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