INFIQC   05475
INSTITUTO DE INVESTIGACIONES EN FISICO- QUIMICA DE CORDOBA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Metastabilities in the human prion protein n-terminal beta-sheet are dictated by the 129 polymorphism
Autor/es:
PAZ SERGIO ALEXIS; CAMERON F. ABRAMS; ERIC VANDEN-EIJNDEN
Lugar:
New Orleans
Reunión:
Congreso; 61st annual meeting biophysical society.; 2017
Resumen:
We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly paramaterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V,D178N) polymorphs have a ground-state conformation with three intact beta-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion ?strain? hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation.