Theoretical Chemistry Accounts

, 131:1287

Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms

Authors

    • Department of ChemistryNew York University
    • Courant Institute of Mathematical SciencesNew York University
  • Karunesh Arora
    • Departments of Chemistry and BiophysicsUniversity of Michigan
  • William A. Beard
    • Laboratory of Structural BiologyNational Institute of Environmental Sciences, National Institutes of Health
  • Samuel H. Wilson
    • Laboratory of Structural BiologyNational Institute of Environmental Sciences, National Institutes of Health
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 catalysis Intrinsic protein dynamics Pre-chemistry conformational adjustments Nucleotidyl transfer DNA polymerase β Catalytic cycle chemical step

Copyright information

© Springer-Verlag Berlin Heidelberg 2012