Using Computer Modeling to Study Prion Diseases

Amyloid diseases, such as Parkinson's, Huntington's and Transmissible spongiform encephalopathy(Prion), have captured considerable public attention recently; all involve the aggregation of proteins in "misfolded" forms. The prion phenomenon, as one kind of amyloid diseases, has gained scientific interest for its non-nuclei acid based, self-replication process: the disease-causing prion protein(PrPSc, also called the scrapie prion protein) can engender reproduction by inducing the normal prion protein( PrPC) to misfold its structure into the scrapie form; the PrPSc itself acts as a template for the PrPC during the reproduction process, and specific nucleic acid sequences are not involved during the reproduction. These properties were also discovered in several non-Mendelian heritable elements in the yeast Saccharomyces cerevisiae[1], thus the term "prion" was spread to certain yeasts and fungi. Rather, the characteristic disease strain information is hypothesized to be stored in the misfolded protein conformation.;Elucidating the process of conversion from PrPC to PrPSc is essential in understanding and finding methods to cure the prion diseases. However, this is very challenging due to the lack of high-resolution experimental data of the PrPSc structure, because of its insoluble and noncrystalline character. Accordingly, computer simulation of theoretical models for the protein structures presents a path forward for understanding and guiding experiment. We examine here with all atom molecular dynamics the unfolding of a proposed left-handed beta helix model for conversion of PrPC to PrP Sc[2].;In this thesis the prion protein aggregation is studied primarily in two regions: The first one is finding a common transition state between the alpha helical structure(AH) at the C-terminus of human PrP C and the metastable left-handed beta helical(LHBH) structure which can possibly template human PrPSc by performing the unfolding simulations to both structures. With molecular dynamics at high temperature 498K, two-dimensional projection of C alpha RMSD plots, cluster analysis, conformational analysis and alignments, the convergence to a common conformation intermediate between the AH and LHBH was observed, which indicates a direct pathway between the two structures without the need to pass through a fully unfolded structure. This result gives us new insights to the conversion between PrP C and PrPSc.;The second one is to search for prion regions in proteins of the Saccharomyces cerevisiae yeasts, using software developed by a collaborator which can propose potential matches of sequence to LHBH structure[3]. This method is based upon a heuristic variant of the dynamic programming (HDP) algorithm used in protein sequence alignment. We scanned 19 proteins proposed to have possible prion behavior in yeast, and used GPU based, explicit solvent, all atom molecular dynamics to assess their stability. Of the 19 starting proteins 9 were identified as being strong candidates for LHBH structure.;Our computational studies using theoretical model on the prion protein aggregation, not only present a microscopic picture of the structural change of the prion proteins, but also may provide insights to the formation of the prion diseases and relevant drug design. These methods are also applicable in choosing good candidates of aggregation prone sequences in proteins before conducting real experiments, thus possibly saving budgets and time in the lab.