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Use of molecular dynamics simulation to explore structural facets of human prion protein with pathogenic mutations

Gargi Borgohain1, Nirnoy Dan2, Sandip Paul1

  • 1Department of Chemistry, Indian Institute of Technology, Guwahati 781039, India.

Biophysical Chemistry
|April 25, 2016
PubMed

Insights

Familial Creutzfeldt-Jakob disease mutations T193I and R148H stabilize prion protein structure. Molecular dynamics simulations reveal altered dynamics and conformations, impacting protein stability and disease mechanisms.

Area of Science:

  • Biophysics
  • Molecular Biology
  • Neuroscience

Background:

  • Prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), arise from mutations in the prion protein.
  • Numerous pathogenic mutations affecting prion protein structure and function are documented.

Purpose of the Study:

  • To investigate the conformational changes and dynamics of prion protein with T193I and R148H mutations using molecular dynamics simulations.
  • To compare the stability and structural behavior of mutated prion proteins against the native form.

Main Methods:

  • Classical molecular dynamics (MD) simulations were employed.
  • Analysis focused on conformational stability, secondary structure content (beta-sheet, helices), and fluctuations.

Main Results:

  • Both T193I and R148H mutations resulted in conformationally steadier prion protein forms compared to the native protein.
  • R148H mutation decreased native beta-sheet content, stabilized the H1 helix, and induced turn regions and coil formation.
  • T193I mutation stabilized the H1 helix, reduced beta-sheet content, and introduced a 310 helix region in H2.
  • The R148H mutation led to a more compact and less fluctuating protein structure.

Conclusions:

  • Prion protein mutations T193I and R148H enhance structural stability but alter protein dynamics and secondary structure.
  • These mutations, particularly R148H, induce significant local structural changes that may influence prion protein aggregation and disease pathogenesis.
Keywords:
Molecular Dynamics SimulationMutationPrion diseasesR148HT193I

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