Prion protein conversion triggered by acidic condition: a molecular dynamics study through different force fields.

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Prions cause fatal neurodegenerative diseases like BSE.
• The structure of the disease-associated prion protein (PrPSc) is not fully understood.
• Prion conversion mechanisms are studied using hypothetical beta-rich structures.

Purpose of the Study:

• To systematically investigate the influence of six different force fields on prion protein structural conversion.
• To assess how acidic and neutral pH conditions affect structural changes.
• To identify reliable force fields for simulating prion protein dynamics.

Main Methods:

• In silico simulation of Syrian hamster cellular prion protein.
• Utilized six distinct force fields: GROMOS96 53a6, GROMOS96 43a1, AMBER99SB, AMBER99SB-ILDN, CHARMM27, and OPLS-AA/L.
• Simulations were performed at both acidic and neutral pH.

Main Results:

• Simulation outcomes showed a strong dependence on the chosen force field.
• Only GROMOS96 53A6 and AMBER99SB successfully predicted high beta-sheet formation at acidic pH.
• These two force fields also adequately reproduced neutral pH conditions.
• Beta-sheet elongation was observed to be driven by the N-terminal tail's movement towards the HB alpha-helix under acidic conditions.

Conclusions:

• The selection of force fields is critical for accurate prion protein structural conversion modeling.
• GROMOS96 53A6 and AMBER99SB are recommended for simulating acidic pH-induced structural changes in prion proteins.
• This study provides a comprehensive comparison of force fields for prion protein structural dynamics.