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Simulation of enzyme–substrate encounter with gated active sites

Nature Structural Biology volume 1, pages 6569 (1994) | Download Citation

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Abstract

We describe a brownian dynamics simulation method that allows investigation of the effects of receptor flexibility on ligand binding rates. The method is applied to the encounter of substrate, glyceraldehyde 3–phosphate, with triose phosphate isomerase, a diffusion–controlled enzyme with flexible peptide loops at its active sites. The simulations show that while the electrostatic field surrounding the enzyme steers the substrate into its active sites, the flexible loops appear to have little influence on the substrate binding rate. The dynamics of the loops may therefore have been optimized during evolution to minimize their interference with the substrate's access to the active sites. The calculated and experimental rate constants are in good agreement.

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Author information

Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstr. 1,69012 Heidelberg, Germany.

    • Rebecca C. Wade
    •  & Eugene Demchuk
  2. Department of Chemistry, University of Houston, Houston, TX 77204-5641, USA.

    • Brock A. Luty
    • , James M. Briggs
    •  & J. Andrew McCammon
  3. Department of Chemistry, University of South Alabama, Mobile, AL 36688.

    • Jeffry D. Madura
  4. Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA

    • Malcolm E. Davis

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DOI

https://doi.org/10.1038/nsb0194-65

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