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Molecular Dynamics Simulations on the Bioactive Molecule of hIAPP22–29 (NFGAILSS) and Rational Drug Design

  • Panagiotis Lagarias
  • Youness Elkhou
  • Jayson Vedad
  • Athina Konstantinidi
  • Adam A. Profit
  • Tahsin F. Kellici
  • Antonios Kolocouris
  • Ruel Z. B. Desamero
  • Thomas Mavromoustakos
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1824)

Abstract

This chapter includes information about the structure in equilibrium of the bioactive molecule hIAPP22–29 (NFGAILSS). The experimental structure was derived using X-ray and its 2D NOESY NMR experiments in d6-DMSO and d-HFIP solvents. This molecule contains eight of the ten amino acids of the 20–29 region of the human islet amyloid polypeptide (hIAPP) often referred as the “amyloidogenic core.” Amyloid deposits are well-known to cause as many as 20 pathological neurodegenerative disorders such as Alzheimer, Parkinson, Huntington, and Creutzfeldt-Jakob. The experimental structure was relaxed using molecular dynamics (MD) in simulation boxes consisting in DMSO and HFIP; the latter not provided by the applied software. The calculations were performed in GPUs and supercomputers, and some basic scripting is described for reference. The simulations confirmed the inter- and intramolecular forces that led to an “amyloidogenic core” observed from NOE experiments. The results showed that in DMSO and HFIP environment, Phe is not in spatial proximity with Leu or Ile, and this is consistent with an amyloidogenic core. However, in an amphipathic environment such as the model lipid bilayers, this communication is possible and may influence peptide amyloidogenic properties. The knowledge gained through this study may contribute to the rational drug design of novel peptides or organic molecules acting by modifying preventing amyloidogenic properties of the hIAPP peptide.

Key words

hIAPP22–29 Aggregation of proteins Molecular dynamics NMR Amyloids 

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Panagiotis Lagarias
    • 1
  • Youness Elkhou
    • 2
    • 3
  • Jayson Vedad
    • 2
    • 3
  • Athina Konstantinidi
    • 1
  • Adam A. Profit
    • 2
    • 3
  • Tahsin F. Kellici
    • 4
  • Antonios Kolocouris
    • 1
  • Ruel Z. B. Desamero
    • 2
    • 3
  • Thomas Mavromoustakos
    • 4
  1. 1.Department of PharmacyNational and Kapodistrian University of Athens, Panepistimiopolis, ZografouAthensGreece
  2. 2.Department of ChemistryYork College and The Institute for Macromolecular AssembliesJamaicaUSA
  3. 3.Ph.D. Programs in Chemistry and BiochemistryThe Graduate Center of the City University of New YorkNew YorkUSA
  4. 4.Division of Organic Chemistry, Department of ChemistryNational and Kapodistrian University of Athens, Panepistimiopolis, ZografouAthensGreece

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