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Simulating structural and thermodynamic properties of carcinogen-damaged DNA.

ABSTRACT: A pair of stereoisomeric covalent adducts to guanine in double-stranded DNA, derived from the reaction of mutagenic and tumorigenic metabolites of benzo[a]pyrene, have been well characterized structurally and thermodynamically. Both high-resolution NMR solution structures and an array of thermodynamic data are available for these 10S (+)- and 10R (-)-trans-anti -[BP]-N(2)-dG adducts in double-stranded deoxyoligonucleotides. The availability of experimentally well-characterized duplexes containing these two stereoisomeric guanine adducts provides an opportunity for evaluating the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method for computing thermodynamic properties from molecular dynamics ensembles. We have carried out 3-ns molecular dynamics simulations, using NMR solution structures as the starting models for the 10S (+)- and 10R (-)-trans-anti-dG adducts in a DNA duplex 11-mer using AMBER 6.0. We employed the MM-PBSA method to compute the free energies, enthalpies, and entropies of the two adducts. Our complete thermodynamic analysis agrees quite well with the full experimental thermodynamic characterization of these adducts, showing essentially equal stabilities of the two adducts. We also calculated the nuclear Overhauser effect (NOE) distances from the molecular dynamics trajectories, and compared them against the experimental NMR-derived NOE distances. Our results showed that the simulated structures are in good agreement with the NMR experimental NOE data. Furthermore, the molecular dynamics simulations provided new structural and biological insights. Specifically, the puzzling observation that the BP aromatic ring system in the 10S (+)-trans-anti-dG adduct is more exposed to the aqueous solvent than the 10R (-)-trans-anti-dG adduct, is rationalized in terms of the adduct structures. The structural and thermodynamic features of these stereoisomeric adducts are also discussed in relation to their reported low susceptibilities to nucleotide excision repair.

SUBMITTER: Yan S

PROVIDER: S-EPMC1302781 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Simulating structural and thermodynamic properties of carcinogen-damaged DNA.

Yan Shixiang S Wu Min M Patel Dinshaw J DJ Geacintov Nicholas E NE Broyde Suse S

Biophysical journal 20030401 4

A pair of stereoisomeric covalent adducts to guanine in double-stranded DNA, derived from the reaction of mutagenic and tumorigenic metabolites of benzo[a]pyrene, have been well characterized structurally and thermodynamically. Both high-resolution NMR solution structures and an array of thermodynamic data are available for these 10S (+)- and 10R (-)-trans-anti -[BP]-N(2)-dG adducts in double-stranded deoxyoligonucleotides. The availability of experimentally well-characterized duplexes containin ...[more]

PMID: 12668423

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Project description:A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4- dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A*, are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.

Project description:We perform path-integral molecular dynamics (PIMD) simulations of H2O and D2O using the q-TIP4P/F model. Simulations are performed at P = 1 bar and over a wide range of temperatures that include the equilibrium (T≥ 273 K) and supercooled (210 ≤T < 273 K) liquid states of water. The densities of both H2O and D2O calculated from PIMD simulations are in excellent agreement with experiments in the equilibrium and supercooled regimes. We also evaluate important thermodynamic response functions, specifically, the thermal expansion coefficient αP(T), isothermal compressibility κT(T), isobaric heat capacity CP(T), and static dielectric constant ε(T). While these properties are in excellent [αP(T) and κT(T)] or semi-quantitative agreement [CP(T) and ε(T)] with experiments in the equilibrium regime, they are increasingly underestimated upon further cooling. It follows that the inclusion of nuclear quantum effects in PIMD simulations of (q-TIP4P/F) water is not sufficient to reproduce the anomalous large fluctuations in density, entropy, and electric dipole moment characteristic of supercooled water. It has been hypothesized that water may exhibit a liquid-liquid critical point (LLCP) in the supercooled regime at P > 1 bar and that such a LLCP generates a maximum in CP(T) and κT(T) at 1 bar. Consistent with this hypothesis and in particular, with experiments, we find a maximum in the κT(T) of q-TIP4P/F light and heavy water at T≈ 230-235 K. No maximum in CP(T) could be detected down to T≥ 210 K. We also calculate the diffusion coefficient D(T) of H2O and D2O using the ring-polymer molecular dynamics (RPMD) technique and find that computer simulations are in remarkable good agreement with experiments at all temperatures studied. The results from RPMD/PIMD simulations are also compared with the corresponding results obtained from classical MD simulations of q-TIP4P/F water where atoms are represented by single interacting sites. Surprisingly, we find minor differences in most of the properties studied, with CP(T), D(T), and structural properties being the only (expected) exceptions.

Dataset Information

Simulating structural and thermodynamic properties of carcinogen-damaged DNA.

Publications

Simulating structural and thermodynamic properties of carcinogen-damaged DNA.

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