Conformational instability of human prion protein upon residue modification: a molecular dynamics simulation study

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Amino acid substitutions are key to understanding protein structure-function relationships.
• Assessing the impact of these substitutions on protein dynamics remains challenging.
• The Arg(208) to His mutation in human prion protein (PrP) is linked to Creutzfeldt-Jakob disease (CJD).

Purpose of the Study:

• To investigate the effects of residue modification on the structural dynamics of human prion protein (PrP).
• To compare the conformational changes induced by Alanine substitution versus neutralization of Arginine at position 208 in PrP.
• To elucidate the molecular mechanisms underlying PrP conformational transitions relevant to CJD.

Main Methods:

• Comparative molecular dynamics (MD) simulations were performed on native PrP and two analogs.
• Three 10 ns MD simulations were conducted on constructs with Alanine substitution (PrPALA) and neutralized Arginine (PrPSB) at position 208.
• Conformational fluctuations and structural alterations were analyzed.

Main Results:

• Neutralizing Arginine at position 208 (PrPSB) induced minor, reversible changes in a flexible loop (residues 167-171).
• Alanine substitution at position 208 (PrPALA) caused irreversible impacts on secondary and tertiary structures.
• These irreversible changes led to instabilities in a remote region (residues 190-195) of the C-terminal helix 2.

Conclusions:

• Deprotonation of Arg(208) has a minimal effect on PrP backbone dynamics.
• Alanine substitution at Arg(208) significantly destabilizes PrP structure, suggesting a mechanism for CJD pathogenesis.
• Conformational changes and altered force distributions due to mutations like Arg(208) to His are critical for CJD development.