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Preorganization and protein dynamics in enzyme catalysis.

P T Ravi Rajagopalan1, Stephen J Benkovic

  • 1Department of Chemistry, Pennsylvania State University, University Park, 16802, USA.

Chemical Record (New York, N.Y.)
|April 5, 2002
PubMed
Summary

Enzyme catalysis relies on protein dynamics, not just transition state stabilization. Protein motions preorganize active sites for faster reactions, as seen in dihydrofolate reductase (DHFR).

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Area of Science:

  • Biochemistry
  • Enzymology
  • Protein Dynamics

Background:

  • Enzyme catalysis explanations have shifted from transition state (TS) stabilization to active site preorganization.
  • Protein dynamic motion is increasingly recognized as crucial for enzyme function and rate enhancement.

Purpose of the Study:

  • To explore the role of protein dynamics in enzyme catalysis, specifically in dihydrofolate reductase (DHFR).
  • To investigate how enzyme active site preorganization and TS stabilization are achieved through protein motions.

Main Methods:

  • Analysis of kinetic, structural, and computational studies on Dihydrofolate Reductase (DHFR).
  • Examination of flexible loop regions and their motions within the DHFR active site.
  • Investigation of potential long-range protein motions influencing catalytic rates.

Main Results:

  • DHFR utilizes flexible loop motions to modulate substrate passage through the active site.
  • Unexpected participation of distant residues in enhancing hydride transfer rates suggests long-range motion importance.
  • Preorganization of the active site, driven by protein dynamics, facilitates substrate binding near the TS geometry.

Conclusions:

  • Protein dynamics play a critical role in enzyme catalysis, complementing or superseding TS stabilization theories.
  • Flexible loops and potentially long-range motions in enzymes like DHFR are key to achieving catalytic efficiency.
  • Understanding protein dynamics is essential for comprehending broader biological processes.

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