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DNA polymerase beta catalysis: are different mechanisms possible?

Ian L Alberts1, Yanli Wang, Tamar Schlick

  • 1Department of Chemistry and Courant Institute of Mathematical Sciences, 251 Mercer Street, New York University, New York, New York 10012, USA.

Journal of the American Chemical Society
|August 19, 2007
PubMed
Summary

Researchers studied DNA polymerase beta (pol beta) mechanisms using QM/MM. The most probable pathway for nucleotide transfer involves initial deprotonation to water, with higher energy barriers for mismatched base pairs, explaining polymerase fidelity.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Computational Chemistry

Background:

  • DNA polymerases are essential for DNA replication and repair.
  • Understanding DNA polymerase mechanisms at the atomic level is key to explaining fidelity.
  • Mammalian DNA polymerase beta (pol beta) is a model X-family polymerase.

Purpose of the Study:

  • To investigate low-energy pathways for nucleotide transfer in pol beta.
  • To compare reaction mechanisms for correct (G:C) versus incorrect (G:G) base pairing.
  • To elucidate the role of the enzymatic environment and solvent in reaction fidelity.

Main Methods:

  • Utilized mixed quantum mechanics/molecular mechanics (QM/MM) techniques.
  • Employed a constrained energy minimization protocol.
  • Modeled the reactive core, enzymatic environment, and explicit solvent effects.

Main Results:

  • The most probable initial step is deprotonation to water, followed by proton migration, with an activation energy of ~15 kcal/mol.
  • Direct deprotonation to nucleotide phosphate or active site Asp residues is energetically less favorable.
  • The rate-determining step is initial deprotonation coupled with nucleophilic attack.
  • Mismatched G:G pairing exhibits a 5 kcal/mol higher activation energy than G:C pairing due to distortions.

Conclusions:

  • The findings support existing mechanisms for DNA polymerase function.
  • Initial deprotonation via water molecules is a critical step in pol beta nucleotide transfer.
  • Active site preorganization influences nucleotide specificity and fidelity across polymerase families.