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Substrate Positioning Dynamics Involves a Non-Electrostatic Component to Mediate Catalysis
Yaoyukun Jiang1, Ning Ding1, Qianzhen Shao1
1Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
The Journal of Physical Chemistry Letters
|December 12, 2023
Summary
Substrate positioning dynamics (SPD) significantly impacts enzyme catalysis through non-electrostatic effects. Optimizing SPD enhances transition state stabilization and catalytic efficiency by favoring reactive conformations.
Area of Science:
- Enzyme kinetics and catalysis
- Biophysical chemistry
- Computational enzymology
Background:
- Substrate positioning dynamics (SPD) influences enzyme catalytic efficiency by orienting substrates in the active site.
- The relative contribution of electrostatic versus non-electrostatic components of SPD to catalysis remains unclear.
Purpose of the Study:
- To investigate the role of the non-electrostatic component of SPD in transition state (TS) stabilization.
- To determine if SPD can independently mediate catalysis with a significant non-electrostatic contribution.
Main Methods:
- Utilized high-throughput enzyme modeling to select Kemp eliminase variants with controlled electrostatics but varied SPD.
- Experimentally characterized kinetic parameters of selected enzyme variants.
- Quantified SPD using a substrate positioning index and calculated TS stabilization free energy.
Main Results:
- Observed a distinct, two-segment linear correlation between TS stabilization free energy and the substrate positioning index.
- Identified a variation of approximately 2 kcal/mol in energy across different SPD profiles.
- The R154W mutant exhibited favorable SPD, increasing reactive conformations and achieving the lowest activation free energy.
Conclusions:
- The non-electrostatic component of substrate positioning dynamics significantly contributes to enzyme catalytic efficiency.
- SPD plays a crucial role in transition state stabilization beyond electrostatic interactions.
- Enzyme engineering strategies can leverage SPD to enhance catalytic performance.
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