NDLI: Minimization of dynamic effects in the evolution of dihydrofolate reductase

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Chemical Science Vol - 7 Issue - 4

Chemical Science Vol - 7 Issue - 3

Chemical Science Vol - 7 Issue - 2

Chemical Science Vol -6

Chemical Science Vol -5

Chemical Science Vol -4

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Minimization of dynamic effects in the evolution of dihydrofolate reductase

Content Provider	Royal Society of Chemistry (RSC)
Author	Tuñón, Iñaki Behiry, Enas Loveridge, E. Joel Allemann, Rudolf K. Luk, Louis Y. P. Ruiz-Pernía, J. Javier Moliner, Vicent
Copyright Year	2016
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 trajectories on the transition state dividing surface. We postulate that these motions are minimized by fine-tuning DHFR flexibility through optimization of the free energy surface of the reaction, such that a nearly static reaction-ready configuration with optimal electrostatic properties is maintained under physiological conditions.
Starting Page	3248
Ending Page	3255
Page Count	8
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	7
Issue Number	5
Journal	Chemical Science
DOI	10.1039/c5sc04209g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Dihydrofolic acid Isotope Enzyme catalysis Thermophile Enzyme Escherichia coli Geobacillus Mesophile Mathematical optimization Protein Thermodynamic free energy
Content Type	Text
Resource Type	Article
Subject	Chemistry

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