Minimization of dynamic effects in the evolution of dihydrofolate reductase

Chemical Science
J Javier Ruiz-PerníaRudolf K Allemann

Abstract

Protein isotope labeling is a powerful technique to probe functionally important motions in enzyme catalysis and can be applied to investigate the conformational dynamics of proteins. Previous investigations have indicated that dynamic coupling is detrimental to catalysis by dihydrofolate reductase (DHFR) from the mesophile Escherichia coli (EcDHFR). Comparison of DHFRs from organisms adapted to survive at a wide range of temperatures suggests that dynamic coupling in DHFR catalysis has been minimized during evolution; it arises from reorganizational motions needed to facilitate charge transfer events. Contrary to the behaviour observed for the DHFR from the moderate thermophile Geobacillus stearothermophilus (BsDHFR), the chemical transformation catalyzed by the cold-adapted bacterium Moritella profunda (MpDHFR) is only weakly affected by protein isotope substitutions at low temperatures, but the isotopically substituted enzyme is a substantially inferior catalyst at higher, non-physiological temperatures. QM/MM studies revealed that this behaviour is caused by the enzyme's structural sensitivity to temperature changes, which enhances unfavorable dynamic coupling at higher temperatures by promoting additional recrossing trajec...Continue Reading

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Citations

Oct 4, 2018·Physical Chemistry Chemical Physics : PCCP·Maite RocaVicent Moliner
May 19, 2019·Applied and Environmental Microbiology·Alan F ScottRudolf K Allemann
Apr 25, 2019·Chembiochem : a European Journal of Chemical Biology·Alan F ScottRudolf K Allemann
Apr 22, 2020·Annual Review of Physical Chemistry·Christopher M Cheatum
Jul 20, 2018·Journal of the Royal Society, Interface·Dušan PetrovićJose M Sanchez-Ruiz
Feb 2, 2021·The Journal of Physical Chemistry. B·Anil R Mhashal, Dan Thomas Major
Jun 5, 2020·Journal of the American Chemical Society·Rory M CreanShina C L Kamerlin
Apr 21, 2021·Chembiochem : a European Journal of Chemical Biology·Aduragbemi S AdesinaRudolf K Allemann
Dec 10, 2016·Journal of the American Chemical Society·Agnieszka KrzemińskaKatarzyna Świderek
Nov 7, 2018·Journal of the American Chemical Society·Anil R MhashalDan Thomas Major
Jul 25, 2018·The Journal of Physical Chemistry. B·Anil R MhashalDan Thomas Major
Oct 31, 2017·Journal of the American Chemical Society·Chethya RanasingheAmnon Kohen

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Methods Mentioned

BETA
circular dichroism

Software Mentioned

Ensemble Averaged Variational Transition State Theory ( EA - V...

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