Helix-coil transition of PrP106-126: molecular dynamic study

Area of Science:

• Biophysics
• Computational Chemistry
• Neuroscience

Background:

• The prion protein (PrP) is implicated in neurodegenerative diseases.
• PrPSc is characterized by a high beta-sheet content, contrasting with the normal PrPC's alpha-helical structure.
• The peptide PrP106-126 is a model system for studying PrP conversion.

Purpose of the Study:

• Investigate the stability of the alpha-helical conformation of the PrP106-126 peptide.
• Elucidate the mechanism of conversion from alpha-helix to random-coil structure.
• Examine the impact of the A117V mutation on peptide stability and conversion.

Main Methods:

• Performed 34 molecular dynamic (MD) simulations.
• Total simulation time of 305 ns.
• Utilized both explicit and implicit solvent models.

Main Results:

• Wild-type PrP106-126 rapidly lost its helical structure at neutral pH within nanoseconds.
• The A117V mutation significantly destabilized the helix, accelerating conversion by ~1 ns.
• The A117V mutant showed a different conversion mechanism, initiating at the C-terminus and involving new hydrophobic interactions.
• Beta-sheet conformation was less stable at acidic pH due to protonation of His(111).

Conclusions:

• The wild-type PrP106-126 helix is unstable and converts rapidly to a random coil.
• The A117V mutation exacerbates helix instability and alters the conversion pathway.
• Hydrophobic interactions play a crucial role in both helix stability and conversion mechanisms.
• pH affects helix stability, particularly through histidine protonation.