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Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes
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Modulating Enzyme Activity by Altering Protein Dynamics with Solvent
Michael R Duff1, Jose M Borreguero2, Matthew J Cuneo3
1Biochemistry & Cellular and Molecular Biology Department , University of Tennessee , Knoxville , Tennessee , United States.
Biochemistry
|June 15, 2018
Summary
Altering enzyme dynamics using organic solvents can control enzyme activity. Suppressing motions in dihydrofolate reductase (DHFR) with isopropanol decreased its hydride transfer rate, demonstrating a link between dynamics and catalysis.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Enzyme activity is influenced by structure and dynamics, but the role of dynamics is debated.
- Controlling enzyme dynamics offers a novel way to modulate enzyme function.
Purpose of the Study:
- To investigate the impact of altered enzyme dynamics on catalytic activity.
- To explore the use of aqueous organic solvent mixtures to control enzyme dynamics.
Main Methods:
- Utilized aqueous mixtures of isopropanol (IPA) to modify enzyme dynamics.
- Employed stopped-flow kinetics to measure reaction rates.
- Used X-ray crystallography and quasi-elastic neutron scattering to analyze enzyme structure and dynamics.
Main Results:
- A 2.2-fold decrease in the hydride transfer rate (khydride) of dihydrofolate reductase (DHFR) was observed at 20% IPA.
- No significant changes in enzyme structure were detected via X-ray crystallography.
- Quasi-elastic neutron scattering confirmed suppressed enzyme motions in the mixed solvent.
Conclusions:
- Enzyme dynamics can be modulated by aqueous organic solvents to control enzyme activity.
- Suppressed dynamics in DHFR lead to reduced catalytic efficiency by limiting access to functional conformational substates.
- This approach offers insights into rate-limiting dynamics in catalysis and has implications for enzyme engineering.
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