Impact of the tail and mutations G131V and M129V on prion protein flexibility.

Within the "protein-only" hypothesis, a detailed mechanism for the conversion of a alpha-helix to beta-sheet structure is unclear. We have investigated the effects of the tail 90-123 and the point mutations G131V and M129V on prion protein conformational plasticity at neutral pH. Molecular dynamics simulations show that the dynamics of the core 124-226 is essentially independent of the tail and that the point mutation G131V does not affect PrP thermodynamic stability. Both mutations, however, enhance the flexibility of residues that participate in the two-step process for prion propagation. They also extend the short beta-sheet in the normal protein into a larger sheet at neutral pH. This finding suggests a critical role of the tail for triggering the topological change. Copyright 2003 Wiley-Liss, Inc.