A study of 2-azido-3,5-dichlorobiphenyl by nano- and picosecond laser flash photolysis and computational methods.

The dynamics of singlet 3,5-dichloro-2-biphenylnitrene and the products of its rearrangement were monitored by pico- and nanosecond laser flash photolysis and the results were consistent with the predictions of DFT and ab initio molecular orbital calculations.     

Ab initio prediction of optical rotation: comparison of density functional theory and Hartree-Fock methods for three 2,7,8-trioxabicyclo[3.2.1]octanes

We report ab initio calculations of the frequency-dependent electric dipole-magnetic dipole polarizabilities, beta(nu), at the sodium D line frequency and, thence, of the specific rotations, [alpha](D), of 2,7,8-trioxabicyclo[3.2.1]octane, 1, and its 1-methyl derivative, 2, using the Density Functional Theory (DFT) and Hartree-Fock/Self-Consistent Field (HF/SCF) methodologies. Gauge-invariant (including) atomic orbitals (GIAOs) are used to ensure origin-independent [alpha](D) values. Using large basis sets which include diffuse functions DFT [alpha](D) values are in good agreement with experimental values (175.8 degrees and 139.2 degrees for (1S,5R)-1 and -2, respectively); errors are in the range 25-35 degrees. HF/SCF [alpha](D) values, in contrast, are much less accurate; errors are in the range 75-95 degrees. The use of small basis sets which do not include diffuse functions substantially lowers the accuracy of predicted [alpha](D) values, as does the use of the static limit approximation: beta(nu) approximately beta(o). The use of magnetic-field-independent atomic orbitals, FIAOs, instead of GIAOs, leads to origin-dependent, and therefore nonphysical, [alpha](D) values. We also report DFT calculations of [alpha](D) for the 1-phenyl derivative of 1, 3. DFT calculations find two stable conformations, differing in the orientation of the phenyl group, of very similar energy, and separated by low barriers. Values of [alpha](D) predicted using two different algorithms for averaging over phenyl group orientations are in good agreement with experiment. In principle, the absolute configuration (AC) of a chiral molecule can be assigned by comparison of the optical rotation predicted ab initio to the experimental value. Our results demonstrate the critical importance of the choice of ab initio methodology in obtaining reliable optical rotations and, hence, ACs, and show that, at the present time, DFT constitutes the method of choice.     

Structure, energetics, vibrational frequencies and charge transfer of base pairs, nucleoside pairs, nucleotide pairs and B-DNA pairs of trinucleotides: ab initio HF/MINI-1 and empirical force field study

Geometries, interaction energies and vibrational frequencies of base pairs, nucleoside pairs and nucleotide pairs were studied by ab initio Hartree-Fock (HF) method using MINI-1 basis set and empirical Cornell et al. force field (AMBER 4.1). A good agreement was found between HF/MINI-1 and AMBER results. In addition, both methods provide reasonable agreement with available high-level ab initio data. Finally, AMBER potential was used to determine the structure, energetics and vibrational frequencies of B-DNA pairs of trinucleotides. Stabilization energies of clusters are lowered when passing from base pairs to nucleoside pairs, nucleotide pairs and to pairs of trinucleotides. The lowest vibrations of base pairs and nucleoside pairs correspond to intermolecular motions of bases, specifically to buckle and propeller motions. In the case of pairs of larger subunits the lowest vibrations are of intramolecular nature (rotation around glycosidic bond, sugar and phosphate vibration). The spectra of these clusters became more complicated and quasi-degenerate. Intermolecular charge transfer between bases in H-bonded and stacked pairs is negligible, while a significant intramolecular charge transfer was observed.     

On the performance of semiempirical MO theory for dipole moments of dye molecules

The dipole moments of a set of 71 simple dye molecules calculated at the ab initio, DFT, and semiempirical levels have been compared. The DFT dipole moments are on average 16% larger than those obtained by MP2/6-31G**. AM1 and PM3 modified with an empirical correction procedure yield dipole moments essentially at the same level of accuracy as the results of non-empirical calculations. INDO/S and CNDO/S are considerably less accurate. Among different versions of spectral methods, the CISD scheme gives the best performance.Electronic Supplementary Material available.     

Coordination and thermodynamics of stable Zn(II) complexes in the gas phase

Ab initio molecular orbital methods in combination with DFT calculations were used to study the structural and thermodynamic properties of 17 complexes containing zinc cation and four first-shell ligands as models of active site of metalloenzymes (e.g. angiotensin converting enzyme, thermolysin). The geometry of the complexes was relaxed by complete optimization by ab initio molecular orbital methods at Hertree-Fock level with 3-21G* basis set. Following single point calculation with tight SCF criteria at the B3LYP level with 6-311+G(2d,p) basis set was used to calculate accurate interaction enthalpies. The structure and thermodynamics of optimized complexes are discussed from the point of view of their biological importance.     

Ab initio conformational analysis of nucleic acid components: intrinsic energetic contributions to nucleic acid structure and dynamics

In recent years, the use of high-level ab initio calculations has allowed for the intrinsic conformational properties of nucleic acid building blocks to be revisited. This has provided new insights into the intrinsic conformational energetics of these compounds and its relationship to nucleic acids structure and dynamics. In this article we review recent developments and present new results. New data include comparison of various levels of theory on conformational properties of nucleic acid building blocks, calculations on the abasic sugar, known to occur in vivo in DNA, on the TA conformation of DNA observed in the complex with the TATA box binding protein, and on inosine. Tests of the Hartree-Fock (HF), second-order M?ller-Plesset (MP2), and Density Functional Theory/Becke3, Lee, Yang and Par (DFT/B3LYP) levels of theory show the overall shape of backbone torsional energy profiles (for gamma, epsilon, and chi) to be similar for the different levels, though some systematic differences are identified between the MP2 and DFT/B3LYP profiles. The east pseudorotation energy barrier in deoxyribonucleosides is also sensitive to the level of theory, with the HF and DFT/B3LYP east barriers being significantly lower (approximately 2.5 kcal/mol) than the MP2 counterpart (approximately 4.0 kcal/mol). Additional calculations at various levels of theory suggest that the east barrier in deoxyribonucleosides is between 3.0 and 4.0 kcal/mol. In the abasic sugar, the west pseudorotation energy barrier is found to be slightly lower than the east barrier and the south pucker is favored more than in standard nucleosides. Results on the TA conformation suggest that, at the nucleoside level, this conformation is significantly destabilized relative to the global energy minimum, or relative to the A- and B-DNA conformations. Deoxyribocytosine would destabilize the TA conformation more than other bases relative to the A-DNA conformation, but not relative to the B-DNA conformation.     

Determination of the structure of chiral molecules using ab initio vibrational circular dichroism spectroscopy

We discuss the theoretical prediction of vibrational circular dichroism (VCD) spectra using ab initio density functional theory (DFT) and the application of this methodology to the determination of the absolute configurations and conformations of chiral molecules.     

The Hydrolysis Mechanism of Formamide Revisited: Comparison Between ab initio, Semiempirical and DFT Results

The hydrolysis of amides is a model reaction to study peptide hydrolysis. This process has been previously considered in the literature at the ab initio level. In this work, we revisit different reaction mechanisms (water-assisted, non-assisted, neutral and acid-catalyzed) with various theoretical methods : semiempirical, ab initio and Density Functional. The ab initio calculations are carried out at a computational level which is substantially higher than in previous studies. We describe the structure of the transition states and discuss the influence of the catalyst. We also compute the activation free energies for these processes at the Density Functional Theory level. Comparison of the methods allows to outline the main trends of these theoretical approaches which may be useful to design new computational strategies for investigating biological reaction mechanisms through the use of combined Quantum Mechanics/Molecular Mechanics methods.     

Ab initio computational study of beta-cellobiose conformers using B3LYP/6-311++G**

The molecular structure of 27 conformers of beta-cellobiose were studied in vacuo through gradient geometry optimization using B3LYP density functionals and the 6-311++G** basis set. The conformationally dependent geometry changes and energies were explored as well as the hydrogen-bonding network. The lowest electronic energy structures found were not those suggested from available crystallographic and NMR solution data, where the glycosidic dihedral angles fall in the region (phi, psi) approximately (40 degrees, -20 degrees ). Rather, 'flipped' conformations in which the dihedral angles are in the range (phi, psi) approximately (180 degrees, 0 degrees ) are energetically more stable by approximately 2.5 kcal/mol over the 'experimentally accepted' structure. Further, when the vibrational free energy, deltaG, obtained from the calculated frequencies, is compared throughout the series, structures with (phi, psi) in the experimentally observed range still have higher free energy ( approximately 2.0 kcal/mol) than 'flipped' forms. The range of bridging dihedral angles of the 'normal' conformers, resulting from the variance in the phi dihedral is larger than that found in the 'flipped' forms. Due to this large flat energy surface for the normal conformations, we surmise that the summation of populations of these conformations will favor the 'normal' conformations, although evidence suggests that polar solvent effects may play the dominant role in providing stability for the 'normal' forms. Even though some empirical studies previously found the 'flipped' conformations to be lowest in energy, these studies have been generally discredited because they were in disagreement with experimental results. Most of the DFT/ab initio conformations reported here have not been reported previously in the ab initio literature, in part because the use of less rigorous theoretical methods, i.e. smaller basis sets, have given results in general agreement with experimental data, that is, they energetically favored the 'normal' forms. These are the first DFT/ab initio calculations at this level of theory, apparently because of the length and difficulty of carrying out optimizations at these high levels.     

Theoretical spectroscopy of model-nonheme [Fe(IV)OL5]2+ complexes in their lowest triplet and quintet states using multireference ab initio and density functional theory methods

The structure, energies and spectroscopic properties of a simple [FeO(NH(3))(5)](2+) model with ground states (3)A(2g) and (5)A(1g) (in approximate C(4v) symmetry) have been studied in some detail using density functional (DFT) and simplified correlated multireference ab initio methods. The results reveal similarities as well as some pronounced differences in the properties of the molecule in the two alternative spin states.     

Density-functional theory and ab initio Hartree-Fork studies on the structural parameters and chemical activity of the free radicals generated by benzoquinone and hydroquinone

Density-functional theory (DFT) calculations were performed for calculation of the theoretical spectra and the chemical activities of free radicals generated by benzoquinone and hydroquinone as well as the transition states, and the calculated spectra were used for the assignment of the frequencies observed in the experimental IR spectra. The calculated geometrical parameters, the predicted IR spectra, and the chemical activities of free radicals and transition states were also compared with those of benzoquinone and hydroquinone. The reactive mechanisms of free radicals generated by benzoquinone and hydroquinone are also discussed using ab initio Hartree-Fork (HF) methods.     

Evaluation of structural and evolutionary contributions to deleterious mutation prediction

Methods for automated prediction of deleterious protein mutations have utilized both structural and evolutionary information but the relative contribution of these two factors remains unclear. To address this, we have used a variety of structural and evolutionary features to create simple deleterious mutation models that have been tested on both experimental mutagenesis and human allele data. We find that the most accurate predictions are obtained using a solvent-accessibility term, the C(beta) density, and a score derived from homologous sequences, SIFT. A classification tree using these two features has a cross-validated prediction error of 20.5% on an experimental mutagenesis test set when the prior probability for deleterious and neutral cases is equal, whereas this prediction error is 28.8% and 22.2% using either the C(beta) density or SIFT alone. The improvement imparted by structure increases when fewer homologs are available: when restricted to three homologs the prediction error improves from 26.9% using SIFT alone to 22.4% using SIFT and the C(beta) density, or 24.8% using SIFT and a noisy C(beta) density term approximating the inaccuracy of ab initio structures modeled by the Rosetta method. We conclude that methods for deleterious mutation prediction should include structural information when fewer than five to ten homologs are available, and that ab initio predicted structures may soon be useful in such cases when high-resolution structures are unavailable.     

Molecular mechanics:the cross-conjugated carbonyl group in heterocyclic compounds. 3. Parameterisation (MM2) of the adjacent C=C bond: evaluation tests

In the MM2 force field, the definition of a new type of carbon (carbonyl atom, when it is cross-conjugated) has led to the reestimation of the mechanical parameters of the adjacent C(O)-O and C(O)-N bonds in fully-conjugated cyclic compouds: !-pyrones, '-lactones, and conjugated "lactams". New parameters, based on the study of 97 bonds, are presented here for the similar adjacent C(O)-C bond in the same compounds. Comparison of calculated bond lengths to experimental X-ray bond lengths shows that, statistically, the results are substantially improved but the dispersion remains large. Full optimisation of the molecules concerned shows that in some cases the errors accumulate on the C(O)-O bond which is more sensitive to errors in the evaluation of its own ? bond order. The origins of the discrepancies are discussed. Using caffeine as a test molecule, the MM2 method with the parameters proposed here, appears less acurate than the ab initio and DFT methods (both with 6-31G**basis) but still better than the semi-empirical methods (AM1-PM3).     

Constructing side chains on near-native main chains for ab initio protein structure prediction

Is there value in constructing side chains while searching protein conformational space during an ab initio simulation? If so, what is the most computationally efficient method for constructing these side chains? To answer these questions, four published approaches were used to construct side chain conformations on a range of near-native main chains generated by ab initio protein structure prediction methods. The accuracy of these approaches was compared with a naive approach that selects the most frequently observed rotamer for a given amino acid to construct side chains. An all-atom conditional probability discriminatory function is useful at selecting conformations with overall low all-atom root mean square deviation (r.m.s.d.) and the discrimination improves on sets that are closer to the native conformation. In addition, the naive approach performs as well as more sophisticated methods in terms of the percentage of chi(1) angles built accurately and the all-atom r. m.s.d., between the native and near-native conformations. The results suggest that the naive method would be extremely useful for fast and efficient side chain construction on vast numbers of conformations for ab initio prediction of protein structure.