title: Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH.
abstract: Bovine spongiform encephalopathy (BSE), or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP), which adopts two conformers; PrPC is the native innocuous form, which is α-helix rich; and PrPSc is the β-sheet rich misfolded form, which is infectious and forms neurotoxic species. Acidic pH induces the conversion of PrPC to PrPSc. We have performed molecular dynamics simulations of bovine PrP at various pH regimes. An acidic pH environment induced conformational changes that were not observed in neutral pH simulations. Putative misfolded structures, with nonnative β-strands formed in the flexible N-terminal domain, were found in acidic pH simulations. Two distinct pathways were observed for the formation of nonnative β-strands: at low pH, hydrophobic contacts with M129 nucleated the nonnative β-strand; at mid-pH, polar contacts involving Q168 and D178 facilitated the formation of a hairpin at the flexible N-terminus. These mid- and low pH simulations capture the process of nonnative β-strand formation, thereby improving our understanding of how PrPC misfolds into the β-sheet rich PrPSc and how pH factors into the process.
authors: Department of Bioengineering, University of Washington, Seattle WA 98195-5013, USA. chengc2@uw.edu.
authors: Chin Jung
authors: CJ
authors: Cheng
authors: Department of Bioengineering, University of Washington, Seattle WA 98195-5013, USA. daggett@uw.edu.
authors: Valerie
authors: V
authors: Daggett
mesh_terms: D000818:Animals; D002417:Cattle; D016643:Encephalopathy, Bovine Spongiform / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D018621:PrPC Proteins / Q000737:chemistry* / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins