Accommodation of a 1S-(-)-Benzo[c]phenanthrenyl-N6-dA Adduct in the Y-Family Dpo4 DNA Polymerase Active Site: Structural Insights through Molecular Dynamics Simu
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- 作者：Lihua Wang ; Min Wu ; S. Frank Yan ; Dinshaw J. Patel ; Nicholas E. Geacintov ; and Suse Broyde
- 刊名：Chemical Research in Toxicology
- 出版年：2005
- 出版时间：March 2005
- 年：2005
- 卷：18
- 期：3
- 页码：441 - 456
- 全文大小：2220K
- 年卷期：v.18,no.3(March 2005)
- ISSN：1520-5010
文摘
Molecular modeling and molecular dynamics simulations have been performed to elucidatefeasible 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, amodel with the aromatic ring system in the polymerase major groove open pocket, and a -1deletion major groove model. All four 2'-deoxyribonucleoside 5'-triphosphates (dNTPs) wereconsidered in the first two cases, and a normal Watson-Crick partner positioned to haveskipped 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 evaluatethe extents of distortion for each system. Overall, our results suggest that the major groovemodel is the least distorted, followed by the -1 deletion model, while the intercalation modelis 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. Theintercalation model appears most likely to impede the polymerase. More broadly, these modelslook reasonable for other PAH metabolite-derived adducts to adenine with similar 1Sstereochemistry. Furthermore, these models suggest how error-prone translesion synthesisby Y-family polymerases might produce mutations that may play a role in the initiation ofcancer.