Abstract
The prion diseases are a family of fatal neurodegenerative diseases associated with the misfolding and accumulation of normal prion protein (PrPC) into its pathogenic scrapie form (PrPSc). Understanding the fundamentals of prion protein aggregation and the molecular architecture of PrPSc is key to unraveling the pathology of prion diseases. Our work investigates the early-stage aggregation of three prion protein peptides, corresponding to residues 120-144 of human (Hu), bank vole (BV), and Syrian hamster (SHa) prion protein, from disordered monomers to β-sheet-rich fibrillar structures. Using 12 μs discontinuous molecular dynamics simulations combined with the PRIME20 force field, we find that the Hu-, BV-, and SHaPrP(120-144) aggregate via multiple nucleation-dependent pathways to form U-shaped, S-shaped, and Ω-shaped protofilaments. The S-shaped HuPrP(120-144) protofilament is similar to the amyloid core structure of HuPrP(112-141) predicted by Zweckstetter. HuPrP(120-144) has a shorter aggregation lag phase than BVPrP(120-144) followed by SHaPrP(120-144), consistent with experimental findings. Two amino acid substitutions I138M and I139M retard the formation of parallel in-register β-sheet dimers during the nucleation stage by increasing side chain-side chain association and reducing side chain interaction specificity. On average, HuPrP(120-144) aggregates contain more parallel β-sheet content than those formed by BV- and SHaPrP(120-144). Deletion of the C-terminal residues 138-144 prevents formation of fibrillar structures in agreement with the experiment. This work sheds light on the amyloid core structures underlying prion strains and how I138M, I139M, and S143N affect prion protein aggregation kinetics.
Highlights
The self-diffusion coefficients in both DMD and molecular dynamics (MD) simulation are calculated using the Einstein equation
The longest time accessed in the single DMD simulation should have been 672 s, which corresponds to 2000 billion collisions
MSDt ϩ ⌬tϭ MSDtϩ d2 ϭ MSDtϩ where ⌬t is the time unit; N is the total number of peptides; d2 is the averaged square displacement of N peptides; and ritϩ⌬t and rit are the coordinates of the ith peptide at t ϩ ⌬t and t
Summary
The self-diffusion coefficients in both DMD and MD simulation are calculated using the Einstein equation. In the “Materials and Methods” section, the conversion of the reduced time unit to a real time unit (⌬t* ϭ 0.072 ns) was incorrect. The correct value should be ⌬t* ϭ 0.96 ns.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have