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Evolutionary conserved Tyr169 stabilizes the β2-α2 loop of the prion protein

D. Huang; A. Caflisch

Journal: J. Am. Chem. Soc.
Year: 2015
Volume: 137
Issue: 8
Pages: 2948-2957
DOI: 10.1021/ja511568m
Type of Publication: Journal Article

aggregation; conformational transition; free energy landscape; molecular dynamics; Prion Diseases; Prions; secondary structure


Experimental evidence indicates that the primary structure of the β2-α2 loop region (residues 165-175) in mammalian prion proteins (PrP) influences the conversion from the cellular species (PrPC) to the β-sheet-rich aggregate. Here, we captured the transition of the β2-α2 loop from 310-helical turn to β turn by unbiased molecular dynamics simulations of the single-point mutant Y169G. Multiple conformations along the spontaneous transition of the mutant were then used as starting point for sampling of the free-energy surface of the wild type and other single-point mutants. Using two different methods for the determination of free energy profiles, we found that the barrier for the 310-helical turn to β turn transition of the wild type is higher by about 2.5 kcal/mol than for the Y169G mutant, which is due to favorable stacking of the aromatic rings of Y169 and F175, and a stable hydrogen bond between the side chains of Y169 and D178. The transition of the β2-α2 loop to β turn increases the solvent-exposure of the hydrophobic stretch 169-YSNQNNF-175. The simulations indicate that the strictly conserved Y169 in mammalian prion proteins stabilizes the 310-helical turn in the β2-α2 loop, thus hindering the conversion to an aggregation-prone conformation.