Theoretical Chemistry Accounts

, 131:1287

Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms

  • Tamar Schlick
  • Karunesh Arora
  • William A. Beard
  • Samuel H. Wilson
Regular Article

DOI: 10.1007/s00214-012-1287-7

Cite this article as:
Schlick, T., Arora, K., Beard, W.A. et al. Theor Chem Acc (2012) 131: 1287. doi:10.1007/s00214-012-1287-7

Abstract

In recent papers, there has been a lively exchange concerning theories for enzyme catalysis, especially the role of protein dynamics/pre-chemistry conformational changes in the catalytic cycle of enzymes. Of particular interest is the notion that substrate-induced conformational changes that assemble the polymerase active site prior to chemistry are required for DNA synthesis and impact fidelity (i.e., substrate specificity). High-resolution crystal structures of DNA polymerase β representing intermediates of substrate complexes prior to the chemical step are available. These structures indicate that conformational adjustments in both the protein and substrates must occur to achieve the requisite geometry of the reactive participants for catalysis. We discuss computational and kinetic methods to examine possible conformational change pathways that lead from the observed crystal structure intermediates to the final structures poised for chemistry. The results, as well as kinetic data from site-directed mutagenesis studies, are consistent with models requiring pre-chemistry conformational adjustments in order to achieve high fidelity DNA synthesis. Thus, substrate-induced conformational changes that assemble the polymerase active site prior to chemistry contribute to DNA synthesis even when they do not represent actual rate-determining steps for chemistry.

Keywords

Enzyme catalysisIntrinsic protein dynamicsPre-chemistry conformational adjustmentsNucleotidyl transferDNA polymerase βCatalytic cycle chemical step

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Tamar Schlick
    • 1
    • 2
  • Karunesh Arora
    • 3
  • William A. Beard
    • 4
  • Samuel H. Wilson
    • 4
  1. 1.Department of ChemistryNew York UniversityNew YorkUSA
  2. 2.Courant Institute of Mathematical SciencesNew York UniversityNew YorkUSA
  3. 3.Departments of Chemistry and BiophysicsUniversity of MichiganAnn ArborUSA
  4. 4.Laboratory of Structural BiologyNational Institute of Environmental Sciences, National Institutes of HealthResearch Triangle ParkUSA