Benzophenone and DNA: Evidence for a Double Insertion Mode and Its Spectral Signature

From explicit solvent molecular dynamics simulations, we probe the existence of two stable and competitive interaction modes between an alternating poly­(dA-dT) decamer and benzophenone, a minor groove adduct and a double insertion structure in which the central base pair is ejected, with hydrogen bonding with proximal groups, locking the DNA–drug complex. The extensive analysis of noncovalent interactions provides a rationale for the existence of this mode, never reported yet between DNA and any organic photosensitizer. We evidence a highly characteristic signature in our simulated circular dichroism spectra that may provide useful guidance for the future experimental efforts, as well as for theoretical investigations aiming at elucidating the energy-transfer mechanism between benzophenone and thymines

Are Dinucleoside Monophosphates Relevant Models for the Study of DNA Intrastrand Cross-Link Lesions? The Example of G[8–5m]T

Oxidatively generated tandem lesions such as G­[8–5m]­T pose a potent threat to genome integrity. Direct experimental studies of the kinetics and thermodynamics of a specific lesion within DNA are very challenging, mostly due to the variety of products that can be formed in oxidative conditions. Dinucleoside monophosphates (DM) involving only the reactive nucleobases in water represent appealing alternative models on which most physical chemistry and structural techniques can be applied. However, it is not yet clear how relevant these models are. Here, we present QM/MM MD simulations of the cyclization step involved in the formation of G­[8–5m]­T from the guanine–thymine (GpT) DM in water, with the aim of comparing our results to our previous investigation of the same reaction in DNA (Garrec, J., Patel, C., Rothlisberger, U., and Dumont, E. (2012) J. Am. Chem. Soc. 134, 2111−2119). We show that, despite the different levels of preorganization of the two systems, the corresponding reactions share many energetic and structural characteristics. The main difference lies in the angle between the G and T bases, which is slightly higher in the transition state (TS) and product of the reaction in water than in the reaction in DNA. This effect is due to the Watson–Crick H-bonds, which are absent in the {GpT+water} system and restrain the relative positioning of the reactive nucleobases in DNA. However, since the lesion is accommodated easily in the DNA macromolecule, the induced energetic penalty is relatively small. The high similarity between the two reactions strongly supports the use of GpT in water as a model of the corresponding reaction in DNA

Intersulfur Distance Is a Key Factor in Tuning Disulfide Radical Anion Vertical UV−Visible Absorption

Maximum absorption wavelengths λ_max for σ* ← σ vertical transition of peptidic disulfide radical anions of increasing complexity were investigated by means of time-dependent density functional theory. Values among a representative set of 17 two-cysteinyl peptides range between 385 and 624 nm (TD-BH&HLYP/DZP++//MP2/DZP++:HF/6-31G* level of theory). This considerable spread contrasts with the usually admitted value of ca. 400−450 nm typically ascribed to two-center three-electron bonds. It is traced back to the large range of equilibrium intersulfur distances <i>d</i>, with values comprised between 2.73 and 3.19 Å. More quantitatively, blue- and red-shifts follow a near-linear regime (slope of 46 nm per 0.1 Å). They can be mapped onto a relaxed scan of l,l-cystine taken as a prototypical system λ_max^ref = 436 nm, 2.79 Å. This result could assist future radioprotectants rational design, with disulfide-linking arcs of controlled geometry. Meanwhile, the presence of a secondary structure motif such as an α-helix does not affect the UV−vis transition

Structure, Dynamics, and Interactions of a C4′-Oxidized Abasic Site in DNA: A Concomitant Strand Scission Reverses Affinities

Apurinic/apyrimidinic (AP) sites constitute the most frequent form of DNA damage. They have proven to produce oxidative interstrand cross-links, but the structural mechanism of cross-link formation within a DNA duplex is poorly understood. In this work, we study three AP-containing d­[GC­G­C­G­C­X­C­G­C­G­C­G]·d­[C­G­C­G­C­G­K­G­C­G­C­GC] duplexes, where X = C, A, or G and K denotes an α,β-unsaturated ketoaldehyde derived from elimination of a C4′-oxidized AP site featuring a 3′ single-strand break. We use explicit solvent molecular dynamics simulations, complemented by quantum chemical density functional theory calculations on isolated X:K pairs. When X = C, the K moiety in the duplex flips around its glycosidic bond to form a stable C:K pair in a near-optimal geometry with two hydrogen bonds. The X = A duplex shows no stable interaction between K and A, which contrasts with AP sites lacking a strand scission that present a preferential affinity for adenine. Only one, transient G:K hydrogen bond is formed in the X = G duplex, although the isolated G:K pair is the most stable one. In the duplex, the stable C:K pair induces unwinding and sharp bending into the major groove at the lesion site, while the internal structure of the flanking DNA remains unperturbed. Our simulations also unravel transient hydrogen bonding between K and the cytosine 5′ to the orphan base X = A. Taken together, our results provide a mechanistic explanation for the experimentally proven high affinity of C:K sites in forming cross-links in DNA duplexes and support experimental hints that interstrand cross-links can be formed with a strand offset

Insights into Intrastrand Cross-Link Lesions of DNA from QM/MM Molecular Dynamics Simulations

DNA damages induced by oxidative intrastrand cross-links have been the subject of intense research during the past decade. Yet, the currently available experimental protocols used to isolate such lesions only allow to get structural information about linked dinucleotides. The detailed structure of the damaged DNA macromolecule has remained elusive. In this study we generated in silico the most frequent oxidative intrastrand cross-link adduct, G­[8,5-Me]­T, embedded in a solvated DNA dodecamer by means of quantum mechanics/molecular mechanics (QM/MM) Car–Parrinello simulations. The free energy of activation required to bring the reactant close together and to form the C–C covalent-bond is estimated to be ∼10 kcal/mol. We observe that the G­[8,5-Me]­T tandem lesion is accommodated with almost no perturbation of the Watson–Crick hydrogen-bond network and induces bend and unwinding angles of ∼20° and 8°, respectively. This rather small structural distortion of the DNA macromolecule compared to other well characterized intrastrand cross-links, such as cyclobutane pyrimidines dimers or cisplatin-DNA complex adduct, is a probable rationale for the known lack of efficient repair of oxidative damages

What Singles Out the G[8–5]C Intrastrand DNA Cross-Link? Mechanistic and Structural Insights from Quantum Mechanics/Molecular Mechanics Simulations

Naturally occurring intrastrand oxidative cross-link lesions have proven to be a potent source of endogenous DNA damage. Among the variety of lesions that can be formed and have been identified, G[8–5]­C damage (in which the C8 atom of a guanine is covalently bonded to the C5 atom of a nearby cytosine belonging to the same strand) occurs with a low incidence yet takes on special importance because of its high mutagenicity. Hybrid Car–Parrinello molecular dynamics simulations, rooted in density functional theory and coupled to molecular mechanics, have been performed to shed light on the cyclization process. The activation free energy of the reacting subsystem embedded in a solvated dodecamer is estimated to be ∼12.4 kcal/mol, which is ∼3 kcal/mol higher than the value for the prototypical G­[8–5m]­T lesion inferred employing the same theoretical framework [Garrec, J., Patel, C., Rothlisberger, U., and Dumont, E. (2012) <i>J. Am. Chem. Soc.</i> <i>134</i>, 2111–2119]. This study also situates the G­[8–5m]­mC lesion at an intermediate activation free energy (∼10.5 kcal/mol). The order of reactivity in DNA (T^• > mC^• > C^•) is reversed compared to that in the reacting subsystems in the gas phase (C^• > mC^• > T^•), stressing the crucial role of the solvated B-helix environment. The results of our simulations also characterize a more severe distortion for G[8–5]C than for methylene-bridged intrastrand cross-links