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Related Experiment Videos

THEMATICS: a simple computational predictor of enzyme function from structure.

M J Ondrechen1, J G Clifton, D Ringe

  • 1Department of Chemistry, Northeastern University, Boston, MA 02115, USA. mjo@neu.edu

Proceedings of the National Academy of Sciences of the United States of America
|October 19, 2001
PubMed
Summary
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Theoretical microscopic titration curves (THEMATICS) can identify protein active-site residues. This method reveals perturbed titration curves predominantly in the active sites of enzymes like TIM, AR, and PMI.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • Identifying active-site residues is crucial for understanding enzyme function and mechanisms.
  • Enzyme structure-activity relationships are complex, with similar structures sometimes catalyzing different reactions, and vice-versa.

Purpose of the Study:

  • To demonstrate the utility of theoretical microscopic titration curves (THEMATICS) for pinpointing active-site residues in proteins.
  • To validate the THEMATICS method across diverse enzymes with varying structures and catalytic functions.

Main Methods:

  • Calculation of theoretical microscopic titration curves for all ionizable residues in target proteins.
  • Analysis of these curves to identify residues exhibiting unusual protonation behavior over a wide pH range.

Related Experiment Videos

  • Comparison of identified residues with known active-site residues in selected enzymes.

    • Main Results:

    • A small percentage (3-7%) of residues across studied enzymes (TIM, AR, PMI) showed perturbed titration curves with a flat region.
    • These perturbed residues were predominantly located within the enzyme active sites.
    • The method proved successful for proteins with diverse chemistries and structures.

    Conclusions:

    • THEMATICS is an effective computational tool for identifying active-site residues in proteins of known structure.
    • Perturbed titration curves serve as reliable indicators of residues critical for enzyme function.
    • The method's applicability extends to a broad range of protein types and biochemical reactions.