Exploring the role of large conformational changes in the fidelity of DNA polymerase beta

Proteins. 2008 Jan 1;70(1):231-47. doi: 10.1002/prot.21668.


The relationships between the conformational landscape, nucleotide insertion catalysis and fidelity of DNA polymerase beta are explored by means of computational simulations. The simulations indicate that the transition states for incorporation of right (R) and wrong (W) nucleotides reside in substantially different protein conformations. The protein conformational changes that reproduce the experimentally observed fidelity are significantly larger than the small rearrangements that usually accompany motions from the reactant state to the transition state in common enzymatic reactions. Once substrate binding has occurred, different constraints imposed on the transition states for insertion of R and W nucleotides render it highly unlikely that both transition states can occur in the same closed structure, because the predicted fidelity would then be many orders of magnitude too large. Since the conformational changes reduce the transition state energy of W incorporation drastically they decrease fidelity rather than increase it. Overall, a better agreement with experimental data is attained when the R is incorporated through a transition state in a closed conformation and W is incorporated through a transition state in one or perhaps several partially open conformations. The generation of free energy surfaces for R and W also allow us to analyze proposals about the relationship between induced fit and fidelity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalysis
  • DNA Polymerase beta / chemistry*
  • DNA Polymerase beta / metabolism
  • Protein Conformation
  • Quantum Theory


  • DNA Polymerase beta