Etude des propriétés énergétiques, conformationnelles et vibrationnelles des déoxyribonucléosides canoniques et modifiés à l'aide des méthodes de la chimie quantique ab initio

L objectif de ce travail a été de présenter une analyse complète des propriétés structurales et vibrationnelles de quelques nucléosides (canonique, mineur et modifié) à l aide des calculs quantiques ab initio effectués par les méthodes DFT et MP2. Les résultats obtenus fournissent un panel large de conformères dans une fourchette étroite de 7 à 10 kcal/mol. Un peu moins de cent conformères déoxynucléotidiques sont stabilisés par une centaine de liaisons hydrogène intramoléculaires de divers types allant des plus fortes (OH O) aux plus faibles incluant des groupements CH. Nous avons montré qu à 298.15 K les nucléosides étudiés possèdent tous un minimum global quasi-dégénéré (estimation faite sur la base de l énergie libre de Gibbs), correspondant en fait à deux conformères. L équilibre conformationnel est décalé vers les bases orientées syn et les conformations Sud (S) du sucre dominent par rapport celles du type Nord (N). L ensemble des paramètres conformationnels a été estimé et la corrélation entre eux a été établie. Les propriétés géométriques, vibrationnelles, topologiques et énergétiques des liaisons H intramoléculaires dans les conformères calculés, ont été déterminées. La reconstitution des spectres IR des conformères de 2 -déoxythymidine et de 2 -déoxyuridine dans la région d élongation de liaisons O-H, sont en accord avec les spectres observés à basse température en matrice de gaze rare. Parmi les nucléosides obtenus théoriquement, seuls trois ressemblent géométriquement à ceux d une chaîne d ADN, en particulier en forme BI, A et BII. Par contre, la 2 -déoxy-6-azacytidine (nucleoside modifié, analogue de la 2 -déoxycytidine) ne peut se présenter que dans un conformère de type A. En examinant les données théoriques obtenues quelques conclusions peuvent être proposées au niveau biologique. En particulier, l effet biologique du nucléoside modifié pourrait correspondre à l inhibition de l action de l ADN polymérase par une orientation inusuelle de la base dans le conformère de type A. D autre part, la similarité entre les caractéristiques des conformères de type ADN de la 2 -déoxythymidine et de la 2 -déoxyuridine (ceux ayant des bases en syn et anti ainsi que ceux correspondant à des états de transition entre ces deux orientations), permet de penser que l enzyme uracile glycosylase distingue entre les deux nucléosides plutôt grâce à leur forme (existence du groupement méthyle en position 5 de la base) que par l influence électronique de ce groupement.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Anion-π\pi interactions in flavoproteins involve a substantial charge-transfer component

Anion–π interactions have been shown to stabilize flavoproteins and to regulate the redox potential of the flavin cofactor. They are commonly attributed to electrostatic forces. Herein we show that anion–flavin interactions can have a substantial charge-transfer component. Our conclusion emanates from a multi-approach theoretical analysis and is backed by previously reported observations of absorption bands, originating from charge transfer between oxidized flavin and proximate cysteine thiolate groups. This partial covalency of anion–flavin contacts renders classical simulations of flavoproteins questionable

The significant role of the intermolecular CH⋯O/N hydrogen bonds in governing the biologically important pairs of the DNA and RNA modified bases: a comprehensive theoretical investigation

<div><p>This paper is a logical continuation of the theoretical survey of the CH⋯O/N specific contacts in the nucleobase pairs using a wide arsenal of the modern methods, which was initiated in our previous study [<i>J. Biomol. Struct. & Dynam.</i>, 2014, <i>32</i>, 993–1022]. It was established that 34 CH⋯O and 7 CH⋯N interactions, that were detected by quantum-chemical calculations in the 39 biologically important pairs involving modified nucleobases, completely satisfy all geometrical, vibrational, electron-topological, in particular Bader’s and “two-molecule” Koch and Popelier’s, Grunenberg’s compliance constants theory and natural bond orbital criteria indicating that they can be identified as true H-bonds. The geometrical criteria of the H-bond formation are fulfilled for all considered CH⋯O/N H-bonds without any exception. It was shown that the classical rule of the stretching vibration shifts does not work in the ~95% cases of the CH⋯O/N H-bonds. Furthermore, significant increase in the frequency of the out-of-plane deformation modes <i>γ</i>(CH) under the formation of CH⋯O/N H-bonds and corresponding changes of their intensities can be also considered as reliable indicators of the H-bonding. We revealed high linear mutual correlations between the electron density, Laplacian of the electron density, H-bond energy at the (3, −1) bond critical points of the CH⋯O/N H-bonds, and different physico-chemical parameters of the CH⋯O/N H-bonds. We suggested that the electron density <i>ρ</i> and the interaction energy <i>E</i>⁽²⁾ of the lone orbital pairs are the most reliable descriptors of the H-bonding. The linear dependence of the H-bond energy <i>E</i>_CH⋯O/N on the electron density <i>ρ</i> was established: <i>E</i>_CH⋯O= 250.263∙<i>ρ</i> – .380/258.255∙<i>ρ</i> – .396 and <i>E</i>_CH⋯N= 196.800∙<i>ρ</i> – .172/268.559∙<i>ρ</i> – .703 obtained at the density functional theory (DFT)/Møller−Plesset (MP2) levels of theory, respectively. The studies of the interaction energies show that the contribution of the CH⋯O and CH⋯N H-bonds into the base pairs stability varies from 3.0/4.2 to 35.1/31.2% and from 3.0/4.3 to 44.4/46.5% at the DFT/MP2 levels of theory, accordingly. Energy decomposition analysis performed for all base pairs involving canonical and modified nucleobases defines the electrostatic attraction and Pauli repulsion as dominant stabilizing forces in all complexes. This observation was additionally confirmed by the results of the QTAIM delocalization indexes analysis. The studies reported here advance our understanding of the biological role of the weak CH⋯O/N H-bonds, that dictates the requirements for the structural and dynamical similarity of the canonical and mismatched pairs with Watson–Crick (WC) geometry, which facilitates their enzymatic incorporation into the DNA double helix during DNA replication. Thus, these H-bonds in the base pairs with WC geometry may be also considered as “the last drop” at the transmission of the electronic signal that launches the chemical incorporation of the incoming nucleoside triphosphate into DNA.</p></div

Nucleic acid quadruplexes based on 8‑halo-9-deazaxanthines : energetics and noncovalent interactions in quadruplex stems

Structural and energetic features of arti fi cial DNA quadruplexes consisting of base tetrads and their stacks with Na + /K + ion(s) inside the central pore and incorporating halogenated derivatives of xanthine, 8- fl uoro-9-deazaxanthine (FdaX), 8- chloro-9-deazaxanthine (CldaX), 8-bromo-9-deazaxanthine (BrdaX), or 8-iodo-9-deazaxanthine (IdaX), have been investigated by modern state-of-the-art computational tools. The DNA (or RNA) quadruplex models based on 8-halo-9-deazaxanthines are predicted to be more stable relative to those with unmodi fi ed xanthine due to the increased stabilizing contributions coming from all three main types of weak interactions (H-bonding, stacking, and ion coordination). Methods for analyzing the electron density are used to understand the nature of forces determining the stability of the system and to gain a predictive potential. Quadruplex systems incorporating polarizable halogen atoms (chlorine, bromine, or iodine) bene fi t signi fi cantly from the stabilizing stacking between the individual tetrads due to an increased dispersion contribution as compared to xanthine and guanine, natural references used. Ion coordination induces a signi fi cant rearrangement of electron density in the quadruplex stem as visualized by electron deformation density (EDD) and analyzed by ETS-NOCV and Voronoi charges. Na + induces larger electron polarization from the quadruplex toward the ion, whereas K + has a higher propensity to electron sharing (identi fi ed by QTAIM delocalization index). We expect that our results will contribute to the development of novel strategies to further modify and analyze the natural G-quadruplex core

Structural and energetic properties of the potential HIV-1 reverse transcriptase inhibitors d4A and d4G:a comprehensive theoretical investigation

<div><p>A comprehensive quantum-chemical investigation of the conformational landscapes of two nucleoside HIV-1 reverse transcriptase inhibitors, 2′,3′-didehydro-2′,3′-dideoxyadenosine (d4A), and 2′,3′-didehydro-2′,3′-dideoxyguanosine (d4G), has been performed at the MP2/6-311++G(d,p)//B3LYP/6-31G(d,p) level of theory. It was found that d4A can adopt 21 conformers within a 5.17 kcal/mol Gibbs free energy range, whereas d4G has 20 conformers within 6.23 kcal/mol at <i>T</i> = 298.15 K. Both nucleosides are shaped by a sophisticated network of specific noncovalent interactions, including conventional (OHO, NHO) and weak (CHO, CHN) hydrogen bonds, as well as dihydrogen (CHHC) contacts. For the OHO, NHO, and CHO hydrogen bonds, natural bond orbital analysis revealed hyperconjugative interactions between the oxygen lone pairs and the antibonding orbital of the donor group. For the CHHC contacts, the electron density migrates from the antibonding orbital, corresponding to the CH group of the sugar residue, to the bonding orbital relative to the same group in the nucleobase. The results confirm the current belief that the biological activity of d4A and d4G is connected with the termination of the DNA chain synthesis in the 5′–3′ direction. Thus, these nucleosides act as competitive HIV-1 reverse transcriptase inhibitors.</p></div

Nucleic Acid Quadruplexes Based on 8‑Halo-9-deazaxanthines: Energetics and Noncovalent Interactions in Quadruplex Stems

Structural and energetic features of artificial DNA quadruplexes consisting of base tetrads and their stacks with Na⁺/K⁺ ion(s) inside the central pore and incorporating halogenated derivatives of xanthine, 8-fluoro-9-deazaxanthine (FdaX), 8-chloro-9-deazaxanthine (CldaX), 8-bromo-9-deazaxanthine (BrdaX), or 8-iodo-9-deazaxanthine (IdaX), have been investigated by modern state-of-the-art computational tools. The DNA (or RNA) quadruplex models based on 8-halo-9-deazaxanthines are predicted to be more stable relative to those with unmodified xanthine due to the increased stabilizing contributions coming from all three main types of weak interactions (H-bonding, stacking, and ion coordination). Methods for analyzing the electron density are used to understand the nature of forces determining the stability of the system and to gain a predictive potential. Quadruplex systems incorporating polarizable halogen atoms (chlorine, bromine, or iodine) benefit significantly from the stabilizing stacking between the individual tetrads due to an increased dispersion contribution as compared to xanthine and guanine, natural references used. Ion coordination induces a significant rearrangement of electron density in the quadruplex stem as visualized by electron deformation density (EDD) and analyzed by ETS-NOCV and Voronoi charges. Na⁺ induces larger electron polarization from the quadruplex toward the ion, whereas K⁺ has a higher propensity to electron sharing (identified by QTAIM delocalization index). We expect that our results will contribute to the development of novel strategies to further modify and analyze the natural G-quadruplex core