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Biomolecules 2014, 4(1), 181-201; doi:10.3390/biom4010181

Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH

Department of Bioengineering, University of Washington, Seattle WA 98195-5013, USA
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Received: 9 January 2014 / Revised: 7 February 2014 / Accepted: 9 February 2014 / Published: 10 February 2014
(This article belongs to the Special Issue Protein Folding and Misfolding)
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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.
Keywords: amyloid disease; mad cow disease; prion protein misfolding; molecular dynamics; PrPSc structure amyloid disease; mad cow disease; prion protein misfolding; molecular dynamics; PrPSc structure
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Cheng, C.J.; Daggett, V. Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH. Biomolecules 2014, 4, 181-201.

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