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


Huang, Danzhi; Caflisch, Amedeo (2015). Evolutionary conserved Tyr169 stabilizes the β2-α2 loop of the prion protein. Journal of the American Chemical Society, 137(8):2948-2957.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:4 March 2015
Deposited On:24 Sep 2015 12:19
Last Modified:05 Apr 2016 19:25
Publisher:American Chemical Society (ACS)
ISSN:0002-7863
Publisher DOI:https://doi.org/10.1021/ja511568m
PubMed ID:25671636

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