Theoretical Chemistry Accounts

, 131:1287 | Cite as

Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms

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


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.


Enzyme catalysis Intrinsic protein dynamics Pre-chemistry conformational adjustments Nucleotidyl transfer DNA polymerase β Catalytic cycle chemical step 



Research described in this Article was supported in part by Philip Morris USA Inc. and Philip Morris International and by NSF award MCB-0316771, and NIH award R01 ES012692 to T.S., and Research Project Numbers Z01-ES050158 and Z01-ES050161 to S.H.W. in the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences and was in association with NIH award 1U19CA105010.


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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

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