Accommodation of a 1S-(-)-benzo[c]phenanthrenyl-N6-dA adduct in the Y-family Dpo4 DNA polymerase active site: structural insights through molecular dynamics simulations

Chem Res Toxicol. 2005 Mar;18(3):441-56. doi: 10.1021/tx049786v.

Abstract

Molecular modeling and molecular dynamics simulations have been performed to elucidate feasible structures in the Y-family Dpo4 DNA polymerase for the 1S-(-)-trans-anti-B[c]Ph-N6-dA adduct, derived from the fjord region polycyclic aromatic hydrocarbon (PAH) benzo[c]phenanthrene. Three types of models were delineated as follows: an intercalation model, a model with the aromatic ring system in the polymerase major groove open pocket, and a -1 deletion major groove model. All four 2'-deoxyribonucleoside 5'-triphosphates (dNTPs) were considered in the first two cases, and a normal Watson-Crick partner positioned to have skipped the modified template was employed as the incoming dNTP in the -1 deletion case. The trajectories derived from the dynamics simulations were analyzed in detail to evaluate the extents of distortion for each system. Overall, our results suggest that the major groove model is the least distorted, followed by the -1 deletion model, while the intercalation model is perturbed the most. The syn-dGTP and syn-dATP mismatches opposite the lesion are well-accommodated in the major groove model, as is the normal Watson-Crick partner dTTP. The intercalation model appears most likely to impede the polymerase. More broadly, these models look reasonable for other PAH metabolite-derived adducts to adenine with similar 1S stereochemistry. Furthermore, these models suggest how error-prone translesion synthesis by Y-family polymerases might produce mutations that may play a role in the initiation of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carcinogens / chemistry*
  • Computer Simulation*
  • DNA Adducts / chemistry*
  • DNA Polymerase beta / chemistry*
  • Models, Molecular*
  • Phenanthrenes / chemistry*

Substances

  • Carcinogens
  • DNA Adducts
  • Phenanthrenes
  • DNA Polymerase beta
  • benzo(c)phenanthrene