Dynamic Diagnosis of Familial Prion Diseases Supports the beta 2-alpha 2 Loop as a Universal Interference Target

Methodology/Principal Findings: Using all-atom molecular dynamics simulations and novel analytical tools we have explored the effect of D178N, V180I, T183A, T188K, E196K, F198S, E200K, R208H, V210I and E211Q mutations on the dynamics of HuPrP(125-228) alpha-fold. We have found that while preserving the native state, all mutations produce dynamic changes which perturb the coordination of the alpha 2-alpha 3 hairpin to the rest of the molecule and cause the reorganization of the patches for intermolecular recognition, as the disappearance of those for conversion inhibitors and the emergence of an interaction site at the beta 2-alpha 2 loop region.