Oxidatively-mediated in silico epimerization of a highly amyloidogenic segment in the human calcitonin hormone (hCT15-19)

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.

[1]  K. Davies.  Protein damage and degradation by oxygen radicals. I. general aspects. , 1987, The Journal of biological chemistry.

[2]  O. V. Galzitskaya,et al.  Radius of gyration as an indicator of protein structure compactness , 2008, Molecular Biology.

[3]  J. Pople,et al.  Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules , 1972 .

[4]  G. Arteel.  Alcohol-induced oxidative stress in the liver: in vivo measurements. , 2008, Methods in molecular biology.

[5]  Won‐Kyo Jung,et al.  Photo-oxidative stress by ultraviolet-B radiation and antioxidative defense of eckstolonol in human keratinocytes. , 2012, Environmental toxicology and pharmacology.

[6]  S. Carney.  Calcitonin and human renal calcium and electrolyte transport. , 1997, Mineral and Electrolyte Metabolism.

[7]  Ross C. Walker,et al.  The implementation of a fast and accurate QM/MM potential method in Amber , 2008, J. Comput. Chem..

[8]  S. Jang,et al.  Computational Study of Human Calcitonin (hCT) Oligomer , 2009 .

[9]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[10]  A. Naito,et al.  NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG. , 2012, Journal of molecular biology.

[11]  T. Clemens,et al.  Evidence that calcitonin stimulates 1,25-dihydroxyvitamin D production and intestinal absorption of calcium in vivo. , 1986, The Journal of clinical investigation.

[12]  C. Cramer,et al.  Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. , 2009, The journal of physical chemistry. B.

[13]  A. Becke.  Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[14]  T. Noda,et al.  Amino Acid Sequence of Eel Calcitonin , 1976 .

[15]  E. Stadtman,et al.  Recent advances in the analysis of oxidized proteins , 2003, Amino Acids.

[16]  K-L Ting,et al.  Combining the GOR V algorithm with evolutionary information for protein secondary structure prediction from amino acid sequence , 2002, Proteins.

[17]  M. Fukayama,et al.  Localization of D-β-Aspartic Acid–Containing Proteins in Human Eyes , 2007 .

[18]  P. Amodeo,et al.  Solution structure of human calcitonin in membrane‐mimetic environment: The role of the amphipathic helix , 1998, Proteins.

[19]  Andrzej Kloczkowski,et al.  GOR V server for protein secondary structure prediction , 2005, Bioinform..

[20]  E. Stadtman.  Protein oxidation and aging , 2006, Science.

[21]  J. Glowacki,et al.  The aging skeleton , 1999 .

[22]  Carlos Simmerling,et al.  Improved Generalized Born Solvent Model Parameters for Protein Simulations. , 2013, Journal of chemical theory and computation.

[23]  B. Fanburg,et al.  Reactive oxygen species in cell signaling. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[24]  T. Lund,et al.  Determination of D/L-amino acids by zero needle voltage electrospray ionisation. , 2008, Rapid communications in mass spectrometry : RCM.

[25]  R. Riek,et al.  3D structure of Alzheimer's amyloid-β(1–42) fibrils , 2005 .

[26]  A. Naito,et al.  Structural diversity of amyloid fibril formed in human calcitonin as revealed by site‐directed 13C solid‐state NMR spectroscopy , 2004, Magnetic resonance in chemistry : MRC.

[27]  R. Hegele,et al.  Linking diabetes with oxidative stress, adipokines, and impaired endothelial precursor cell function. , 2012, The Canadian journal of cardiology.

[28]  Andreas Hoenger,et al.  Identification of a novel ‘aggregation‐prone’/‘amyloidogenic determinant’ peptide in the sequence of the highly amyloidogenic human calcitonin , 2013, FEBS letters.

[29]  Ross C. Walker,et al.  An overview of the Amber biomolecular simulation package , 2013 .

[30]  G. A. Jeffrey,et al.  An Introduction to Hydrogen Bonding , 1997 .

[31]  Ruth Nussinov,et al.  Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: significant role of Asn ladder. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Pople,et al.  Self‐Consistent Molecular‐Orbital Methods. IX. An Extended Gaussian‐Type Basis for Molecular‐Orbital Studies of Organic Molecules , 1971 .

[33]  Maria Cristina Gaudiano,et al.  Early stages of salmon calcitonin aggregation: effect induced by ageing and oxidation processes in water and in the presence of model membranes. , 2005, Biochimica et biophysica acta.

[34]  D. Butterfield,et al.  Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's A beta(1--42) and A beta(25--35). , 2001, Journal of the American Chemical Society.

[35]  Gert Vriend,et al.  Everyday , 2020, Oxford Research Encyclopedia of Literature.

[36]  Y. Kan,et al.  Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice , 2010, Annals of the rheumatic diseases.

[37]  D. Tsikas,et al.  Oxidative stress and human diseases: Origin, link, measurement, mechanisms, and biomarkers , 2009, Critical reviews in clinical laboratory sciences.

[38]  S. Czene,et al.  The nucleotide pool is a significant target for oxidative stress. , 2006, Free radical biology & medicine.

[39]  Juliet M. Taylor,et al.  Neuroinflammation and oxidative stress: Co-conspirators in the pathology of Parkinson’s disease , 2013, Neurochemistry International.

[40]  Dayag Sheykhkarimli,et al.  Molecular ageing: free radical initiated epimerization of thymopentin--a case study. , 2014, The Journal of chemical physics.

[41]  V. Adam,et al.  Electrochemical study of DNA damaged by oxidation stress. , 2013, Combinatorial chemistry & high throughput screening.

[42]  J. Straub,et al.  Global energy minimum searches using an approximate solution of the imaginary time Schroedinger equation , 1993 .

[43]  Mark S. Gordon,et al.  Self‐consistent molecular orbital methods. XXIII. A polarization‐type basis set for second‐row elements , 1982 .

[44]  M. Pondel,et al.  Calcitonin and calcitonin receptors: bone and beyond , 2000, International journal of experimental pathology.

[45]  P. C. Hariharan,et al.  The influence of polarization functions on molecular orbital hydrogenation energies , 1973 .

[46]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[47]  P. Y. Chou,et al.  Empirical predictions of protein conformation. , 1978, Annual review of biochemistry.

[48]  B. Viskolcz,et al.  Quantum chemical analysis of the unfolding of a penta-alanyl 3(10)-helix initiated by HO(•), HO2(•) and O2(-•). , 2011, The journal of physical chemistry. B.

[49]  T. Moliné,et al.  Oxidative stress and cancer: An overview , 2013, Ageing Research Reviews.

[50]  Quantum Thermal Annealing with Renormalization: Application to a Frustrated Model Protein , 2001 .

[51]  B. Viskolcz,et al.  Conformation-dependent ˙OH/H2O2 hydrogen abstraction reaction cycles of Gly and Ala residues: a comparative theoretical study. , 2012, The journal of physical chemistry. B.

[52]  I. Komáromi,et al.  The Effect of Newly Developed OPLS-AA Alanyl Radical Parameters on Peptide Secondary Structure. , 2012, Journal of chemical theory and computation.

[53]  A. Amadei,et al.  Aggregation of small peptides studied by molecular dynamics simulations , 2006, Proteins.

[54]  H. Hultin,et al.  HYDROXYL RADICAL MODIFICATION OF FISH MUSCLE PROTEINS , 1994 .

[55]  J. Gibrat,et al.  GOR method for predicting protein secondary structure from amino acid sequence. , 1996, Methods in enzymology.

[56]  K. Chou,et al.  Prediction of beta-turns. , 1979, Journal of protein chemistry.

[57]  Baroni,et al.  Conjugate gradient minimization of the energy functional: A new method for electronic structure calculation. , 1989, Physical review. B, Condensed matter.

[58]  J. Stevenson.  Regulation of calcitonin and parathyroid hormone secretion by oestrogens. , 1982, Maturitas.

[59]  B. Viskolcz,et al.  The effect of oxidative stress on the bursopentin peptide structure: a theoretical study. , 2014, Physical chemistry chemical physics : PCCP.

[60]  S. Tsunoda,et al.  Localization of D-β-Aspartyl Residue-Containing Proteins in Various Tissues , 2009, International journal of molecular sciences.