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

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.