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Structural characterization of codon 129 polymorphism in prion peptide segments (PrP127-132) using the Markov State

Wycliffe Omwansu1, Robinson Musembi1, Solomon Derese2

  • 1Department of Physics, Faculty of Science and Technology, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya.

Journal of Molecular Graphics & Modelling
|January 2, 2025
PubMed

Insights

The PRNP codon 129 polymorphism influences prion diseases. Molecular dynamics simulations reveal distinct structural changes and stability differences between methionine (M129) and valine (V129) variants, impacting disease susceptibility.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • The human prion protein gene (PRNP) exhibits polymorphism at codon 129, with common alleles encoding methionine (M129) or valine (V129).
  • This PRNP codon 129 polymorphism is linked to genetic variations and susceptibility to prion diseases, including variant Creutzfeldt-Jakob disease (vCJD).
  • The prion fragment 127-132 (PrP127-132) is specifically implicated, with its polymorphic nature at codon 129 influencing disease development.

Purpose of the Study:

  • To investigate the early structural changes associated with the PRNP codon 129 polymorphism.
  • To understand the conformational heterogeneity and polymorphic behavior of the PrP127-132 chain.

Main Methods:

  • Molecular dynamics (MD) simulations were employed to model the structural dynamics.
  • Markov state model (MSM) analysis was utilized to identify metastable states and kinetic pathways.

Main Results:

  • MD simulations revealed a spectrum of structural transitions influenced by the codon 129 polymorphism.
  • MSM analysis predicted distinct metastable states and kinetic networks for the polymorphic chains.
  • The PrP-M129 variant exhibited greater stability, characterized by reduced random-coiled motions, salt bridge formation, and increased native contacts.
  • The PrP-V129 variant showed enhanced random motion and lacked a stabilizing salt bridge, potentially contributing to its pathogenicity.

Conclusions:

  • The PRNP codon 129 polymorphism induces significant structural and dynamic differences in the PrP127-132 fragment.
  • These structural variations, particularly the stability differences between M129 and V129, provide insights into prion disease susceptibility and progression.
  • The study highlights the importance of conformational heterogeneity in understanding prion protein behavior and disease mechanisms.
Keywords:
Markov state modelsMolecular dynamics simulationsPrP-M129PrP-V129PrP127-132

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