Perspective: Pre-chemistry conformational changes in DNA polymerase mechanisms

Tamar Schlick, Karunesh Arora, William A. Beard, Samuel H. Wilson

Research output: Contribution to journalArticlepeer-review

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, substrateinduced conformational changes that assemble the polymerase active site prior to chemistry contribute to DNA synthesis even when they do not represent actual ratedetermining steps for chemistry.

Original languageEnglish (US)
Article number1287
Pages (from-to)1-8
Number of pages8
JournalTheoretical Chemistry Accounts
Volume131
Issue number12
DOIs
StatePublished - 2012

Keywords

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

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

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