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Freezing a single distal motion in dihydrofolate reductase
Alessandro Sergi1, James B Watney, Kim F Wong
1Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
The Journal of Physical Chemistry. B
|February 14, 2006
Summary
Enzyme motion is crucial for hydride transfer. Constraining enzyme movement significantly increases the energy barrier, slowing down reactions by altering conformational sampling.
Area of Science:
- Biochemistry
- Computational Biology
- Enzyme Kinetics
Background:
- Enzyme catalysis relies on dynamic conformational changes.
- Understanding how enzyme motion affects reaction rates is key to enzyme engineering.
Purpose of the Study:
- To investigate the impact of constraining enzyme motion on hydride transfer in dihydrofolate reductase.
- To elucidate the relationship between conformational sampling and catalytic activity.
Main Methods:
- Hybrid quantum/classical molecular dynamics simulations.
- Analysis of free energy barriers and conformational sampling.
- Investigating the effect of distal residue constraints.
Main Results:
- A single distal constraint increased the free energy barrier for hydride transfer by ~3 kcal/mol.
- Constraining motion altered equilibrium dynamics and conformational sampling.
- The reactant state showed increased donor-acceptor distance, reducing transition state probability.
Conclusions:
- Fast thermal fluctuations are essential for enzyme-facilitated hydride transfer.
- Altering conformational sampling via constraints significantly impacts enzyme catalytic activity.
- Enzyme dynamics play a critical role in reaction rates, occurring on experimentally relevant timescales.
