Theoretical Characterization of the H-Bonding and Stacking Potential of Two Nonstandard Nucleobases Expanding the Genetic Alphabet.

We report a quantum chemical characterization of the non-natural (synthetic) H-bonded base pair formed by 6-amino-5-nitro-2(1H)-pyridone (Z) and 2-aminoimidazo[1,2-a]-1,3,5-triazin-4(8H)-one (P). The Z:P base pair, orthogonal to the classical G:C base pair, has been introduced into DNA molecules to expand the genetic code. Our results indicate that the Z:P base pair closely mimics the G:C base pair in terms of both structure and stability. To clarify the role of the NO2 group on the C5 position of the Z base, we compared the stability of the Z:P base pair with that of base pairs having different functional groups at the C5 position of Z. Our results indicate that the electron-donating/-withdrawing properties of the group on C5 have a clear impact on the stability of the Z:P base pair, with the strong electron-withdrawing nitro group achieving the largest stabilizing effect on the H-bonding interaction and the strong electron-donating NH2 group destabilizing the Z:P pair by almost 4 kcal/mol. Finally, our gas-phase and in-water calculations confirm that the Z-nitro group reinforces the stacking interaction with its adjacent purine or pyrimidine ring.

Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and Its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules.

Non-natural (synthetic) nucleobases, including 7-ethynyl- and 7-triazolyl-8-aza-7-deazaadenine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7-deaza modification of the adenine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanine when paired to cytosine. To stress further the H-bonding pairing in the modified adenine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.

Structural stability, acidity, and halide selectivity of the fluoride riboswitch recognition site.

Using static and dynamics DFT methods we show that the Mg(2+)/F(-)/phosphate/water cluster at the center of the fluoride riboswitch is stable by its own and, once assembled, does not rely on any additional factor from the overall RNA fold. Further, we predict that the pKa of the water molecule bridging two Mg cations is around 8.4. We also demonstrate that the halide selectivity of the fluoride riboswitch is determined by the stronger Mg-F bond, which is capable of keeping together the cluster. Replacing F(-) with Cl(-) results in a cluster that is unstable under dynamic conditions. Similar conclusions on the structure and energetics of the cluster in the binding pocket of fluoride-inhibited pyrophosphatase suggest that the peculiarity of fluoride is in its ability to establish much stronger metal-halide bonds.

Exploring new generations of ruthenium olefin metathesis catalysts: the reactivity of a bis-ylidene ruthenium complex by DFT.

Density functional theory calculations were used to predict the behaviour of a potential novel architecture of olefin metathesis catalysts, in which one of the neutral ligands of classical Ru-based catalysts, e.g. a phosphine or an N-heterocyclic carbene, is replaced by an alkylidene group. Introduction of a second alkylidene ligand favors dissociation of the remaining phosphine and the overall energy profile for the metathesis using ethylene as the probe substrate reveals that the proposed bis-alkylidene complexes might match the requirements of a good performing olefin metathesis catalyst.

π-Face donation from the aromatic N-substituent of N-heterocyclic carbene ligands to metal and its role in catalysis.

In this work, we calculate the redox potential in a series of Ir and Ru complexes bearing a N-heterocyclic carbene (NHC) ligand presenting different Y groups in the para position of the aromatic N-substituent. The calculated redox potentials excellently correlate with the experimental ΔE(1/2) potentials, offering a handle to rationalize the experimental findings. Analysis of the HOMO of the complexes before oxidation suggests that electron-donating Y groups destabilize the metal centered HOMO. Energy decomposition of the metal-NHC interaction indicates that electron-donating Y groups reinforce this interaction in the oxidized complexes. Analysis of the electron density in the reduced and oxidized states of representative complexes indicates a clear donation from the C(ipso) of the N-substituents to an empty d orbital on the metal. In case of the Ru complexes, this mechanism involves the Ru-alkylidene moiety. All of these results suggest that electron-donating Y groups render the aromatic N-substituent able to donate more density to electron-deficient metals through the C(ipso) atom. This conclusion suggests that electron-donating Y groups could stabilize higher oxidation states during catalysis. To test this hypothesis, we investigated the effect of differently donating Y groups in model reactions of Ru-catalyzed olefin metathesis and Pd-catalyzed C-C cross-coupling. Consistent with the experimental results, calculations indicate an easier reaction pathway if the N-substituent of the NHC ligand presents an electron-donating Y group.

The intriguing modeling of cis-trans selectivity in ruthenium-catalyzed olefin metathesis.

In this study we have investigated computationally the origin of the cis-trans selectivity in the Ru-catalyzed cross metathesis (CM) of a prototype monosubstituted olefin, i.e., propene. Our calculations suggest that the origin of the preferential formation of trans-olefins is in the product release step, which prevents the initially formed cis-olefin from escaping the metal, and returns it to the reaction pool until the trans-olefin is formed.

Periodic DFT modeling of bulk and surface properties of MgCl2.

MgCl(2) is the preferred support for the industrial Ziegler-Natta catalysts, and is believed to act as a template for the epitactic chemisorption of the active Ti species. As the first step of a thorough computational modeling of these systems, we studied the bulk and surface structure of the ordered alpha and beta phases of MgCl(2) by means of periodic DFT (B3LYP) methods using localized basis sets. The layer structure of both phases was reproduced satisfactorily with the inclusion of a (small) empirical dispersion correction ("DFT-D") as a practical method to describe the attraction between the layers. Surface models were studied on slabs with adequate thickness. It appears that various surfaces exposing 5-coordinated Mg are very similar in energy and are the lowest non-trivial surfaces. Cuts exposing 4-coordinated Mg are significantly less stable; both kinetic and equilibrium models of crystal growth indicate that they should normally not be formed to a significant extent. "Nano-ribbons" of single, flat chains of MgCl(2), sometimes proposed as components of the disordered delta phase, were also evaluated, but are predicted to be unstable to rearrangement. Implications for the role of MgCl(2) as catalyst support are discussed.