Interpreting Hydrogen-Deuterium Exchange Events in Proteins Using Atomistic Simulations: Case Studies on Regulators of G-Protein Signaling Proteins

The Journal of Physical Chemistry. B
Hossein MohammadiaraniHarish Vashisth

Abstract

Hydrogen-deuterium exchange (HDX) experiments are widely used in studies of protein dynamics. To predict the propensity of amide hydrogens for exchange with deuterium, several models have been reported in which computations of amide-hydrogen protection factors are carried out using molecular dynamics (MD) simulations. Given significant variation in the criteria used in different models, the robustness and broader applicability of these models to other proteins, especially homologous proteins showing distinct amide-exchange patterns, remains unknown. The sensitivity of the predictions when MD simulations are conducted with different force-fields is yet to tested and quantified. Using MD simulations and experimental HDX data on three homologous signaling proteins, we report detailed studies quantifying the performance of seven previously reported models (M1-M7) of two general types: empirical and fractional-population models. We find that the empirical models show inconsistent predictions but predictions of the fractional population models are robust. Contrary to previously reported work, we find that the solvent-accessible surface area of amide hydrogens is a useful metric when combined with a new metric defining the distances o...Continue Reading

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Citations

Nov 13, 2019·The Journal of Biological Chemistry·Anne GershensonPatrick L Wintrode
Oct 23, 2019·The Journal of Biological Chemistry·Joseph B O'BrienDavid L Roman
Jul 1, 2020·Biochemical Society Transactions·Andy M LauArgyris Politis
Feb 2, 2021·The Journal of Biological Chemistry·Anne GershensonPatrick L Wintrode
Jan 1, 2021·The Journal of Chemical Physics·Justin T Seffernick, Steffen Lindert
Mar 30, 2021·Journal of Chemical Theory and Computation·Daniel R MarzolfSteffen Lindert
Feb 28, 2020·Biophysical Journal·Richard T BradshawLucy R Forrest
Aug 26, 2020·The Journal of Physical Chemistry. B·Serdal KirmizialtinD Thirumalai
Oct 13, 2021·Biochemistry·Luis Busto-MonerAaron R Dinner

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