title: Evolutionary conserved Tyr169 stabilizes the β2-α2 loop of the prion protein.
abstract: 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 (PrP(C)) 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.
authors: Department of Biochemistry University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors: Danzhi
authors: D
authors: Huang
authors: Amedeo
authors: A
authors: Caflisch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D007700:Kinetics; D051379:Mice; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry; D014443:Tyrosine
chemical_list: D010446:Peptide Fragments; D011328:Prions; D012997:Solvents; D014443:Tyrosine