Theoretical Modeling of Molecular Mechanisms, Time Scales and Strains in Prion Diseases

Abstract : We have obtained significant results modeling: (1) the structure of the minimal infectious prion oligomer as a domain swapped beta helical trimer; (2) metal binding to the prion protein showing results consistent with measured affinities and suggesting a detailed molecular role for the protection of the normal prion form against conversion to the infectious scrapies form when copper is bound to a particular site; (3) kinetics of yeast prion aggregation in vitro illustrating the role of fission; (4) kinetic analysis of transgenic mice time course data for anchorless cellular prions, indicating (a) that the membrane is necessary for exponential growth of infectious aggregate, and (b) that the elongation rate of anchorless prions is likely more rapid than anchored ones. In the coming year we will explore the role of our domain swapped model for 1) understanding strains, 2) understanding a subset of point mutations known to induce disease for those who inherit them, 3) possible docking of octarepeats to the beta helical trimers and their role in prion conversion, 4) additional metal binding to the prion protein (iron, sodium, and copper at H111), and 5) the role of the membrane in inducing exponential growth of infectivity.