Alpha,beta-D-CNA induced rigidity within oligonucleotides.

Introduction of alpha,beta-D-CNA featuring canonical values of the torsional angles alpha and beta within oligonucleotides leads to an overall stabilization and improved rigidity of the duplex DNA as demonstrated by UV experiments, circular dichroism and corroborated by molecular dynamics simulations.

Examining the performance of DFT methods in uranium chemistry: does core size matter for a pseudopotential?

We have investigated the performance of DFT in U(VI) chemistry. A large, representative selection of functionals has been tested, in combination with two ECPs developed in Stuttgart that have different-sized cores (60 and 78 electrons for U). In addition, several tests were undertaken with another 14 electron pseudopotential, which was developed in Los Alamos. The experimental database contained vibrational wavenumbers, thermochemical data, and (19)F chemical shifts for molecules of the type UF(6-n)Cl(n). For the prediction of vibrational wavenumbers, the large-core RECP (14 electrons) gives results that are at least as good as those obtained with the small-core RECP (32 electrons). GGA functionals are as successful as hybrid GGA for vibrational spectroscopy; typical errors are only a few percent with the Stuttgart pseudopotentials. For thermochemistry, hybrid versions of DFT are more successful than GGA, LDA, or meta-GGA. Marginally better results are obtained with a 32 electron ECP than with 14; since the experimental uncertainties are at least 25 kJ/mol for each reaction, the best functionals give results that are essentially indistinguishable from experiment. However, large-basis CCSD(T) results match experiment better than any DFT that we examined. Our findings for NMR spectroscopy are rather disappointing; no combination of pseudopotential, functional, and basis yields even a qualitatively correct prediction of trends in the (19)F chemical shifts of UF(6-n)Cl(n) species. Results yielded by the large-core RECP are, in general, slightly less bad than those obtained with the small core. We conclude that DFT cannot be recommended for predictions of NMR spectra in this series of compounds, though this conclusion should not be generalized. Our most important result concerns the good performance of the large-core Stuttgart pseudopotential. Given its computational efficiency, we recommend that it be used with DFT methods for the prediction of molecular geometries, vibrational frequencies, and thermochemistry of a given oxidation state. The hybrid GGA functionals MPW1PW91 and PBE0 give the best results overall.

Theoretical study of specific hydrogen-bonding effects on the bridging P-OR bond strength of phosphate monoester dianions.

It has been proposed that the driving force for the initial phosphoryl transfer step of protein tyrosine phosphatases (PTPases) could be activation of the substrate ROPO32- by means of an enforced hydrogen-bonding interaction between an aspartic general acid and the bridging oxygen atom O (Zhang et al. Biochemistry 1995, 34, 16088-16096). The potential catalytic effect of this type of interaction, with regard to P-OR bond cleavage, was investigated computationally through simple model systems in which an efficient intramolecular hydrogen bond can take place between a H-bond donor group and the bridging oxygen atom of the dianionic phosphate. The dielectric effect of the environment (epsilon = 1, 4, and 78) was also explored. The results indicate that this interaction causes significant lengthenings of the scissile P-OR bond in all media but with more extreme effects observed in the low dielectric fields epsilon = 1 and epsilon = 4. It is interesting that, in all cases examined, this interaction actually contributes to stabilize the reactant state while causing its P-OR bond to lengthen. Overall, our results support the idea that this specific hydrogen-bonding situation might well be used by PTPases as an important driving force for promoting phosphoryl transfer reactions through highly dissociative transition states.

Linear uranium complexes X2UL5 with L=cyanide, isocyanate: DFT evidence for similarities between uranyl (X=O) and uranocene (X=Cp) derivatives.

A DFT study of the isostructural compounds [UO2L5](n-) with n=3-5 and linear [Cp2UL5](m-) with m=1-3 has been carried out for two different anionic ligands. Structurally stable structures are obtained for all systems. The coordination competition between cyanide (CN(-)) and isocyanide (NC(-)) as well as between cyanate (OCN(-)) and isocyanate (NCO(-)) has been studied in the uranyl case. A clear preference for cyanide and isocyanate complexes is reported. The coordination of five ligands in the equatorial plane is rationalised by the analysis of the MO diagram of both systems. Moreover, the qualitative comparison of the two MO diagrams shows a high similarity in agreement with the isolobality concept. The existence of linear [Cp2UL5](-) organometallic U(VI) complexes is thus proposed, as well as the possibility of obtaining complexes of both types for U(VI) and U(V) with OCN(-) ligands. In addition, the U(IV) linear metallocene is calculated to be stable for the latter ligand.

Theoretical evaluation of the substrate-assisted catalysis mechanism for the hydrolysis of phosphate monoester dianions.

Quantum chemistry methods coupled with a continuum solvation model have been applied to evaluate the substrate-assisted catalysis (SAC) mechanism recently proposed for the hydrolysis of phosphate monoester dianions. The SAC mechanism, in which a proton from the nucleophile is transferred to a nonbridging phosphoryl oxygen atom of the substrate prior to attack, has been proposed in opposition to the widely accepted mechanism of direct nucleophilic reaction. We have assessed the SAC proposal for the hydrolysis of three representative phosphate monoester dianions (2,4-dinitrophenyl phosphate, phenyl phosphate, and methyl phosphate) by considering the reactivity of the hydroxide ion toward the phosphorus center of the corresponding singly protonated monoesters. The reliability of the calculations was verified by comparing the calculated and the observed values of the activation free energies for the analogous S(N)2(P) reactions of F- with the monoanion of the monoester 2,4-dinitrophenyl phosphate and its diester analogue, methyl 2,4-dinitrophenyl phosphate. It was found that the orientation of the phosphate hydrogen atom has important implications with regard to the nature of the transition state. Hard nucleophiles such as OH- and F- can attack the phosphorus atom of a singly protonated phosphate monoester only if the phosphate hydrogen atom is oriented toward the leaving-group oxygen atom. As a result of this proton orientation, the SAC mechanism in solution is characterized by a small Brønsted coefficient value (beta(lg)=-0.25). This mechanism is unlikely to apply to aryl phosphates, but becomes a likely possibility for alkyl phosphate esters. If oxyanionic nucleophiles of pK(a)<11 are involved, as in alkaline phosphatase, then the S(N)2(P) reaction may proceed with the phosphate hydrogen atom oriented toward the nucleophile. In this situation, a large negative value of beta(lg) (-0.95) is predicted for the substrate-assisted catalysis mechanism.

Theoretical studies of the hydroxide-catalyzed P-O cleavage reactions of neutral phosphate triesters and diesters in aqueous solution: examination of the changes induced by H/Me substitution.

DFT calculations and dielectric continuum methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of representative phosphate triesters and diesters, including trimethyl phosphate (TMP), dimethyl 4-nitrophenyl phosphate (DMNPP), dimethyl hydrogen phosphate (DMHP), and the dimethyl phosphate anion (DMP-). The reliability of the calculations is supported by the excellent agreement observed between the calculated and the experimentally determined activation enthalpies for phosphate triesters with poor (TMP) and good (DMNPP) leaving groups. The results obtained for the OH- + DMHP and OH- + DMP- reactions are also consistent with all the available experimental information concerning the hydrolysis reaction of dimethyl phosphate anion at pH > 5. By performing geometry optimizations in the dielectric field (epsilon = 78.39), we found that OH- can attack the phosphorus atom of DMHP without capturing its proton only if the O-H bond of DMHP is oriented opposite the attacking OH- group. In these conditions, the rate for OH- attack on DMHP was found to be approximately 10(3)-fold faster than that for OH- attack on TMP. The calculated rate acceleration induced by the phosphoryl proton corresponds to the maximum rate effect expected from kinetic studies. Overall, our calculations performed on the dimethyl phosphate ester predict that, contrary to what is generally observed for RNA and aryl phosphodiesters, the water-promoted P-O cleavage reaction of DNA should dominate the base-catalyzed reaction at pH 7. These results are suggestive that nucleases may be less proficient as catalysts than has recently been suspected.