Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Frontiers in Molecular Biosciences
Anna S KamenikKlaus R Liedl

Abstract

Proteolytic susceptibility during endolysosomal degradation is decisive for allergic sensitization. In the major birch pollen allergen Bet v 1 most protease cleavage sites are located within its secondary structure elements, which are inherently inaccessible to proteases. The allergen thus must unfold locally, exposing the cleavage sites to become susceptible to proteolysis. Hence, allergen cleavage rates are presumed to be linked to their fold stability, i.e., unfolding probability. Yet, these locally unfolded structures have neither been captured in experiment nor simulation due to limitations in resolution and sampling time, respectively. Here, we perform classic and enhanced molecular dynamics (MD) simulations to quantify fold dynamics on extended timescales of Bet v 1a and two variants with higher and lower cleavage rates. Already at the nanosecond-timescale we observe a significantly higher flexibility for the destabilized variant compared to Bet v 1a and the proteolytically stabilized mutant. Estimating the thermodynamics and kinetics of local unfolding around an initial cleavage site, we find that the Bet v 1 variant with the highest cleavage rate also shows the highest probability for local unfolding. For the stabilize...Continue Reading

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Citations

Jan 30, 2021·Frontiers in Molecular Biosciences·Florian HoferKlaus R Liedl
Nov 15, 2020·The Journal of Chemical Physics·Anna S KamenikKlaus R Liedl
Sep 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Anna S KamenikBrian K Shoichet

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Methods Mentioned

BETA
X-ray
NMR
PCA

Software Mentioned

MOE
tICA
cpptraj
pytraj
Bet
MOE ( Molecular Operating Environment )
GROMACS
AMBER
AmberTools19
pyEMMA

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