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• W2079193823 endingPage "1123" @default.
• W2079193823 startingPage "1108" @default.
• W2079193823 abstract "The potent mutagen/carcinogen benzo[a]pyrene (B[a]P) is activated to (+)-anti-B[a]PDE, which induces a variety of mutations (e.g., G → T, G → A, etc.) via its major adduct [+ta]-B[a]P−N2-dG. One hypothesis is that adducts (such as [+ta]-B[a]P−N2-dG) induce different mutations via different conformations, probably when replicated by different lesion-bypass DNA polymerases (DNAPs). We showed that Escherichia coli DNAP V was responsible for G → T mutations with [+ta]-B[a]P-N2-dG in a 5‘-TGT sequence (Yin et al., (2004) DNA Repair 3, 323), so we wish to study conformations of this adduct/sequence context by molecular modeling. The development of a CHARMM-based molecular dynamics (MD) simulations protocol with free-energy calculations in the presence of solvent and counterions is described. A representative base-pairing and base-displaced conformation of [+ta]-B[a]P−N2-dG in the 5‘-TGT sequence are used: (1) BPmi5, which has the B[a]P moiety in the minor groove pointing toward the base on the 5‘-side of the adduct, and (2) Gma5, which has the B[a]P moiety stacked with the surrounding base pairs and the dG moiety displaced into the major groove. The MD output structures are reasonable when compared to known NMR structures. Changes in DNA sequence context dramatically affect the biological consequences (e.g., mutagenesis) of [+ta]-B[a]P−N2-dG. Consequently, we also developed a MD-based free-energy perturbation (FEP) protocol to study DNA sequence changes. FEP involves the gradual “fading-out” of atoms in a starting structure (A) and “fading-in” of atoms in a final structure (B), which allows a realistic assessment of the energetic and structural changes when two structures A and B are closely related. Two DNA sequence changes are described: (1) 5‘-TGT → 5‘-TGG, which involves two steps [T:A → T:C → G:C], and (2) 5‘-TGT → 5‘-TGC, which involves three steps [T:A → T:2AP → C:2AP → C:G], where 2AP (2-aminopurine) is included, because T:2AP and C:2AP retain more-or-less normal pairing orientations between complementary bases. FEP is also used to evaluate the impact that a 5‘-TGT to 5‘-UGT sequence change might have on mutagenesis with [+ta]-B[a]P-N2-dG. In summary, we developed (1) a CHARMM-based molecular dynamics (MD) simulations protocol with free-energy calculations in the presence of solvent and counterions to study B[a]P-N2-dG adducts in DNA duplexes, and (2) a MD-based free-energy perturbation (FEP) protocol to study DNA sequence context changes around B[a]P−N2-dG adducts." @default.
• W2079193823 created "2016-06-24" @default.
• W2079193823 creator A5009778646 @default.
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• W2079193823 date "2005-06-23" @default.
• W2079193823 modified "2023-10-14" @default.
• W2079193823 title "Free-Energy Perturbation Methods to Study Structure and Energetics of DNA Adducts: Results for the Major N²-dG Adduct of Benzo[<i>a</i>]pyrene in Two Conformations and Different Sequence Contexts" @default.
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• W2079193823 doi "https://doi.org/10.1021/tx049646l" @default.
• W2079193823 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16022503" @default.
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