Preventing misfolding of the prion protein by trimethylamine N-oxide

Transmissible spongiform encephalopathies are a class of fatal neurodegenerative diseases linked to the prion protein. The prion protein normally exists in a soluble, globular state (PrP^C) that appears to participate in copper metabolism in the central nervous system and/or signal transduction. Infection or disease occurs when an alternatively folded form of the prion protein (PrP^Sc) converts soluble and predominantly α-helical PrP^C into aggregates rich in β-structure. The structurally disordered N-terminus adopts β-structure upon conversion to PrP^Sc at low pH. Chemical chaperones, such as trimethylamine N-oxide (TMAO), can prevent formation of PrP^Sc in scrapie-infected mouse neuroblastoma cells [Tatzelt, J., et al. (1996) EMBO J. 15, 6363-6373]. To explore the mechanism of TMAO protection of PrP^C at the atomic level, molecular dynamics simulations were performed under conditions normally leading to conversion (low pH) with and without 1 M TMAO. In PrP^C simulations at low pH, the helix content drops and the N-terminus is brought into the small native β-sheet, yielding a PrP^Sc-like state. Addition of 1 M TMAO leads to a decreased radius of gyration, a greater number of protein-protein hydrogen bonds, and a greater number of tertiary contacts due to the N-terminus forming an Ω-loop and packing against the structured core of the protein, not due to an increase in the level of extended structure as with the PrP^C to PrP^Sc simulation. In simulations beginning with the "PrP^Sc-like" structure (derived from PrP^C simulated at low pH in pure water) in 1 M TMAO, similar structural reorganization at the N-terminus occurred, disrupting the extended sheet. The mechanism of protection by TMAO appears to be exclusionary in nature, consistent with previous theoretical and experimental studies. The TMAO-induced N-terminal conformational change prevents residues that are important in the conversion of PrP^C to PrP^Sc from assuming extended sheet structure at low pH.