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The interstrand N(super 2), N(super 2)-dG DNA cross-linking chemistry of the acrolein-derived gamma-OH-1,N(super 2) propandeoxyguanosine (gamma-OH-PdG) adduct in the 5'-CpG-3' sequences is monitored within a dodecamer duplex by NMR spectroscopy. When the gamma-OH-PdG adduct contained within the 5'-CpG-3' sequence is annealed into the duplex DNA opposite T, a mixture of the 1,N(super 2)-dG cyclic adduct, the aldehyde, and the diol, but no cross-link, is observed.

The structure of the stereochemically favored (R)-[gamma]-hydroxytrimethylene [N.sup.2]-dG:[N.sup.2]-dG interstran DNA cross-link in the 5'-CpG-3' DNA sequence is described. The formation of the hydrogen bond has explained the thermal stability of the carbinolamine interstrand cross-link and the stereochemical preference for the (R) configuration of the cross-link.

The combination of chemical, spectroscopic, and computational analysis of chemistry of interstrand cross-links which are possibly generated in DNA as secondary1,[N.sup.2]-gamma-hydroxypropano-dG adducts of the alpha, beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxy-2E-nonenal (4-HNE) is described. The processing of interstrand cross-links and their roles in the etiology of human disease is discussed.

The criterion for the adsorption of the quantum gases [super 4]He and [H.sub.2] at zero temperature is evaluated and expressed as a relationship between a threshold value of the well-depth of the adsorption potential and the hard core diameter of the gas-surface pair potential. The studies have shown that the criterion for film adsorption is consistent with analogous criteria for films wetting to occur.

The synthesis of naphthyridinols with various alkyl side chains, including a C(7)-dialkyl naphthyridinols with the [alpha]-tocopherol side chain is presented.

Protein crystallization is a necessary but time-consuming and difficult step in structure determination by crystallography. The rate-limiting step of crystallization is nucleation, where protein monomers in solution cluster in an ordered fashion to form a stable nucleus. Here, we propose the use of gold nanoparticles to accelerate nucleation and enhance crystal formation. We tested whether gold nanoparticles can facilitate nucleation by interacting with target proteins and inducing favorable clustering. We used differently sized gold nanospheres and gold nanostars to crystallize hen egg-white lysozyme. Our results indicated that gold nanoparticles significantly increased the number of crystallization conditions (by about 20%). Spherical and larger gold particles were found to be more efficient. Furthermore, the use of gold nanoparticles did not have any adverse effect on data collection or structure determination. Our findings indicate that the use of nanoparticles as protein nucleation-inducing reagents can greatly accelerate structure determination by X-ray crystallography. [ABSTRACT FROM AUTHOR]

The benz[a]anthracene (BA)-modified oligodeoxynucleotide had intercalated the BA moiety from the major groove between R,S,R,S A6.T17 and C5.G18. In this position, the aromatic rings of BA inserted into the duplex structure with the terminal ring threading the duplex and facing toward the minor groove direction. BA, a member of the PAH class of chemical mutagens, is a major component of automobile exhaust, coal tar, atmospheric pollution and cigarette smoke.

Acrolein reacts with dG to form hydroxylated 1 ,N[sup2]-propanodeoxyguanosine (OH-PdG) adducts. Most abundant are the epimeric 3-(2-deoxy-β-D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hyfroxypyrimido[1,2a] purin-10(3H)-ones, commonly referred to as the γ-OH-PdG adducts. When placed complementary to deoxycytosine in duplex DNA, these undergo rearrangement to the N[sup2]-(3-oxopropyl)-dG aldehyde. The latter forms diastereomeric interstrand N[sup2]-dG:N[sup2]-dG cross-links in the 5'-CpG-3' sequence. Here we report the structure of the stereochemically favored (R)-γ-hydroxytrimethylene N[sup2]-dG:M-dG interstrand DNA cross- link in 5'-d(G[sup1] C[sup2]T[sup3]A[sup4]G[sup5]C[sup6]X[sup7]A[sup8]G[sup9]T[sup10]C[sup11]C[sup12])-3'∙ 5'-d(G[sup13]G[sup14]A[sup15]C[sup16]T[sup17]C[sup18]Y[supl9]C[sup20]T[sup21]A[sup22]G[sup23]C[sup24])-3' (X7 is the dG linked to the α-carbon of the carbinolamine linkage, and Y[sup19] is the dG linked to the γ-carbon of the carbinolamine linkage; the cross-link is in the 5'-CpG-3' sequence). The structure was characterized using isotope-edited [sup15]N nuclear Overhauser enhancement spectroscopy heteronuclear single quantum correlation (NOESY-HSQC) NMR, in which the exocyclic amines at X[sup7] or Y[sup19] were [sup15]N-labeled. Analyses of NOE intensities involving Y[sup19] N[sup2]H indicated that the (R)-γ-hydroxytrimethylene linkage was the major cross-link species, constituting 80-90% of the cross-link. The X[sup7] and Y[sup19] imino resonances were observed at 65 °C. Additionally, for the 5'-neighbor base pair G[sup5]C[sup20], the G[sup5] imino resonance remained sharp at 55 °C but broadened at 65 °C. In contrast, for the 3'-neighbor A[sup8]∙T[sup17] base pair, the T[sup17] imino resonance was severely broadened at 55 °C. Structural refinement using NOE distance restraints obtained from isotope-edited 15N NOESY-HSQC data indicated that the (R)-γ-hydroxytrimethylene linkage maintained the C[sup6]∙Y[sup19] and X[sup7]∙C[sup18] base pairs with minimal structural perturbations. The (R)-γ-hydroxytrimethylene linkage was located in the minor groove. The X[sup7] N[sup2] and Y[sup19] N[sup2] atoms were in the gauche conformation with respect to the linkage, which maintained Watson-Crick hydrogen bonding of the cross-linked base pairs. The anti conformation of the hydroxyl group with respect to C' of the tether minimized steric interaction and, more importantly, allowed the formation of a hydrogen bond between the hydroxyl group and C[sup20] O[sup2] located in the 5'-neighboring base pair G[sup5]∙C[sup20]. The formation of this hydrogen bond may, in part, explain the thermal stability of this carbinolamine interstrand cross-link and the stereochemical preference for the (R) configuration of the cross-link. [ABSTRACT FROM AUTHOR]

Various methods are evaluated for their ability to calculate accurate van der Waals (VDW) dispersion forces between nanoclusters. We compare results for spheres using several methods:  the simple Hamaker two-body method, the Lifshitz (DLP) theory with the Derjaguin approximation, the Langbein result for spheres, and our “coupled dipole method” (CDM). The assumptions and shortcomings of each method are discussed. The CDM accounts for all n-body forces, does not assume a continuous and homogeneous dielectric function in each material, accounts for the discreteness of atoms in the particles, can be used for particles of arbitrary shape, and can exactly include the effects of various media. At present, the CDM does not account for retardation. It is shown that even for spheres, methods other than the CDM often give errors of 20% or more for VDW dispersion forces between typical dielectric materials. A related calculation for metals reveals an error in the Hamaker two-body result of nearly a factor of 2. [ABSTRACT FROM AUTHOR]

The interstrand N²,N²-dG DNA cross-linking chemistry of the acrolein-derived γ-OH-1,N²- propanodeoxyguanosine (γ-OH-PdG) adduct in the 5'-CpG-3' sequence was monitored within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific 13C- and 15N-edited experiments. At equilibrium 40% of the DNA was cross-linked, with the carbinolamine form of the cross-link predominating. The cross-link existed in equilibrium with the non-crosslinked N²-(3-oxo-propyl)-dG aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The 1 ,N²-dG cyclic adduct was not detected. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonding at both of the tandem C·G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonding at one or both of the tandem cross-linked C·G base pairs. When the γ-OH-PdG adduct contained within the 5'-CpG-3' sequence was instead annealed into duplex DNA opposite T, a mixture of the 1 ,N²-dG cyclic adduct, the aldehyde, and the diol, but no cross-link, was observed. With this mismatched duplex, reaction with the tetrapeptide KWKK formed DNA-peptide cross-links efficiently. When annealed opposite dA, γ-OH- PdG remained as the 1 ,N²-dG cyclic adduct although transient epimerization was detected by trapping with the peptide KWKK. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and perhaps other α,β-unsaturated aldehydes. These sequence-specific carbinolamine crosslinks are anticipated to interfere with DNA replication and contribute to acrolein-mediated genotoxicity. [ABSTRACT FROM AUTHOR]

Examines structure-activity relationships for a series of site-specific adenyl N6 polycyclic aromatic hydrocarbon (PAH) adducts. Benz[a]anthracene (BA) as PAH component of coal tar; Solution conformation of the BA SRSR(61,2) adduct; Stability of the intercalated BA SRSR(61,2) adduct.

Examines the role of polycyclic aromatic hydrocarbon bay region ring in modulating DNA adduct structure. Comparison of the benz[a]anthracene non-bay region with the bay region of the benzo[a]pyrene and benz[a]anthracene; Role of region ring in the base stacking interactions; Correlation of structural differences and site-specific mutagenesis data.

Recently we demonstrated that the C(7)-unsubstituted tetrahydro-1,8-naphthyridin-3-ol has more than an order of magnitude better peroxyl radical trapping activity than α-tocopherol (α-TOH) in inhibited autoxidations in benzene. In order to prepare analogues more structurally related to α-TOH for further studies in vitro and in vivo, we developed synthetic approaches to C(7)-monoalkyl and C(7)-dialkyl analogues using a sequence involving (1) AgNO3-mediated hydroxymethyl radical addition to 1,8-naphthyridine, (2) regioselective alkyllithium addition by cyclic chelation in a nonpolar solvent, (3) iodination of the naphthyridine at C(3), and (4) CuI-medidated benzyloxylation of the aryl iodide followed by catalytic hydrogenolysis. An α-TOH isostere was prepared by a Wittig coupling of a C16 side chain identical to that of α-TOH to the naphthyridinols. The C(7)-mono- and dialkyl analogues exhibited more than an order of magnitude higher antioxidant activity (kinh = (5.3-6.1) × 107 M-1 s-1) than α-TOH (kinh = 0.35 × 107 M-1 s-1) in benzene, as determined by a newly developed peroxyl radical clock. In addition to the strong antioxidant activity in benzene, the closest α-TOH analogue (naphthyridinol-based tocopherol, N-TOH) showed excellent inhibition of the oxidation of cholesteryl esters in human low-density lipoprotein and spared endogenous α-TOH in these experiments. Lateral diffusion of N-TOH in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes was comparable to that of α-TOH, suggesting that it will have good antioxidant characteristics in both membranes and lipoproteins. Furthermore, a binding assay using a fluorescent tocopherol analogue showed that N-TOH binds to recombinant human tocopherol transfer protein better than α-TOH itself, suggesting that distribution of unnatural antioxidants such as N-TOH in vivo is possible. [ABSTRACT FROM AUTHOR]