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

Background: Mutations in the cellular prion protein associated to
familial prion disorders severely increase the likelihood of its
misfolding into pathogenic conformers. Despite their postulation as
incompatible elements with the native fold, these mutations rarely
modify the native state structure. However they variably have impact on
the thermodynamic stability and metabolism of PrP(C) and on the
properties of PrP(Sc) aggregates. To investigate whether the pathogenic
mutations affect the dynamic properties of the HuPrP(125-229) alpha-fold
and find possible common patterns of effects that could help in
prophylaxis we performed a dynamic diagnosis of ten point substitutions.
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.
Conclusions/Significance: Our results suggest that pathogenic mutations
share a common pattern of dynamical alterations that converge to the
conversion of the beta 2-alpha 2 loop into an interacting region that
can be used as target for interference treatments in genetic diseases.