Density functional theory calculations of optical rotation: employment of ADZP and its comparison with other basis sets

Density function theory calculations of frequency dependent optical rotations ([alpha]omega) for 30 rigid chiral molecules are reported. Calculations have been carried out at the sodium D line frequency, using the augmented double zeta valence quality plus polarization functions (ADZP) basis set and the BP86 nonhybrid and B3LYP hybrid functionals. Gauge-invariant atomic orbitals were used to guarantee origin-independent values of [alpha]D. Comparison between corresponding results obtained with nonhybrid and hybrid functionals as well as with theoretical optical rotations reported in the literature is done. Excited electronic states of three molecules are also discussed in light of circular dichroism spectra and B3LYP and BP86 calculated excitation energies and rotatory strengths. One verifies that the B3LYP/ADZP results are in better agreement with experiment.     

Tetrahydroisoquinolines acting as dopaminergic ligands. A molecular modeling study using MD simulations and QM calculations

A molecular modeling study on 16 1-benzyl tetrahydroisoquinolines (BTHIQs) acting as dopaminergic ligands was carried out. By combining molecular dynamics simulations with ab initio and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of BTHIQs interacting with the human dopamine D2 receptor (D2 DR) is reported here, providing a clear picture of the binding interactions of BTHIQs from both structural and energetic viewpoints. Molecular aspects of the binding interactions between BTHIQs and the D2 DR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental pKi values was obtained, predicting the potential dopaminergic effect of non-synthesized BTHIQs.     

Ab initio self-consistent field and potential-dependent partial equalization of orbital electronegativity calculations of hydration properties of N-acetyl-N'-methyl-alanineamide

Using a recently developed parallel computation algorithm, ab initio self-consistent field (SCF) calculations were carried out to estimate the relative hydration energies for 12 low-energy conformations of N-acetyl-N'-methyl-alanineamide. The requisite SCF calculations were carried out using 6-31G and 6-31G* basis sets, both in the absence and presence of a perturbing potential arising from a model solvent. The alpha R, alpha L, polyproline II (PII), and pi helical conformations were preferentially stabilized by the solvent potential, whereas conformations with intramolecular hydrogen-bonding C5 and C7 were preferred in the gas phase. Average vicinal nmr coupling constants (JNH-C alpha H), calculated using the total energies of the various solvated conformations, were consistent with observed coupling constants for this peptide in aqueous solution. Substantial alteration of the solute charge density occurred upon equilibration with the reaction field, as was exemplified in changes both in the molecular dipole moments and in atom-centered multipoles, when the molecule was transferred from a medium of low dielectric constant to one of high dielectric constant. In order to model these changes in charge density with an empirical scheme, we have implemented a novel monopolar representation of the solute charge density based on a potential-dependent form of partial equalization of orbital electronegativities (PDPEOE). In the atom-centered point charge PDPEOE representation, charge flows from one region of the solute to another in response to external fields. Hydration energies calculated using the PDPEOE representation are similar to those calculated by the SCF procedure. Also, the PDPEOE calculations yielded changes in molecular dipole moments upon solvation that agreed closely with the changes in the calculated ab initio SCF dipole moments.     

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.     

High-level ab initio calculations on the energetics of low-lying spin states of biologically relevant transition metal complexes: a first progress report

Although DFT is the unrivaled method of choice for quantum chemical studies of bioinorganic problems, little is known about its ability to predict the energetics of the low-lying electronic states of transition metal complexes. The first high-level ab initio calculations aimed at calibrating DFT vis-a-vis this issue indicate that, despite its many successes, DFT is far from infallible. In the short term, additional calibration of DFT against more elaborate ab initio methods remains an important goal for computational bioinorganic researchers. In the longer term, we are optimistic that high-level ab initio methods such as CASPT2 and CCSD(T) will be regularly used to study realistic molecules of genuine biochemical interest.     

Ab initio modeling of small, medium, and large loops in proteins.

This study presents different procedures for ab initio modeling of peptide loops of different sizes in proteins. Small loops (up to 8--12 residues) were generated by a straightforward procedure with subsequent "averaging" over all the low-energy conformers obtained. The averaged conformer fairly represents the entire set of low-energy conformers, root mean square deviation (RMSD) values being from 1.01 A for a 4-residue loop to 1.94 A for an 8-residue loop. Three-dimensional (3D) structures for several medium loops (20--30 residues) and for two large loops (54 and 61 residues) were predicted using residue-residue contact matrices divided into variable parts corresponding to the loops, and into a constant part corresponding to the known core of the protein. For each medium loop, a very limited number of sterically reasonable C(alpha) traces (from 1 to 3) was found; RMSD values ranged from 2.4 to 5.9 A. Single C(alpha) traces predicted for each of the large loops possessed RMSD values of 4.5 A. Generally, ab initio loop modeling presented in this work combines elements of computational procedures developed both for protein folding and for peptide conformational analysis.     

Ab initio multireference study of Hetero-Diels-Alder reaction of buta-1,3-diene with alkyl glyoxylates

Hetero-Diels-Alder (HDA) reaction of methyl glyoxylate with buta-1,3-diene has been investigated using multireference methods (complete active space SCF and multi-reference perturbation theory) and compared with several single-reference methods (including DFT) often used in calculations of catalysed [4+2] cycloadditions. Concerted and stepwise mechanisms, found in the literature, are compared. It is shown, that the stepwise mechanism may be a result of choosing unbalanced active space. Such choice leads to very close singlet and triplet states in the intermediate geometry - an artificial effect, that disappears if properly balanced active space is used (here, we use active space of 12 orbitals and 12 electrons). Conclusions concerning the mechanism and usefulness of the applied methodology are drawn, which might be important for theoretical investigation of stereoselectivity and specificity of catalysts for the HDA reaction. Figure Hetero-Diels-Alder reaction of alkyl glyoxylates with buta-1,3-diene, investigated using multi- and single-reference ab initio methods Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Conformational preferences of hypermodified nucleoside lysidine (k2C) occurring at "wobble" position in anticodon loop of tRNA(Ile)

Conformational preferences of hypermodified nucleoside, 4-amino-2-(N(6)-lysino)-1-(beta-D-ribofuranosyl) pyrimidinium (Lysidine or 2-lysyl cytidine), usually designated as k(2)C, have been investigated theoretically by the quantum chemical perturbative configuration interaction with localized orbitals (PCILO) method. The zwitterionic, non-zwitterionic, neutral, and tautomeric forms have been studied. Automated geometry optimization using molecular mechanics force field (MMFF), semi-empirical quantum chemical PM3, and ab initio molecular orbital Hartree-Fock SCF quantum mechanical calculations have also been made to compare the salient features. The predicted most stable conformations of zwitterionic, non-zwitterionic, neutral, and tautomeric form are such that in each of these molecules the orientation of lysidine moiety (R) is trans to the N(1) of cytidine. The preferred base orientation is anti (chi = 3 degrees ) and the lysine substituent folds back toward the ribose ring. This results in hydrogen bonding between the carboxyl oxygen O(12a) of lysine moiety and the 2'-hydroxyl group of ribose sugar. In all these four forms of lysidine O(12a)...H-C(9) and O(12b)...H-N(11) interactions provide stability to respective stable conformers. Watson-Crick base pairing of lysidine with A is feasible only with the tautomeric form of usual anti oriented lysidine. This can help in recognition of AUA codon besides in avoiding misrecognition of AUG.     

An energetic correlation of ab initio and NMR studies of the 3'-gauche effect in 3'-substituted thymidines

A straightforward correlation of our experimental NMR findings on 3'-substituted thymidine derivatives with that of the ab initio calculations shows that (i) the delta Go298kNRM of N reversible S equilibrium in nucleoside can be predicted from the ab initio calculated delta ES-N obtained from 6-311++G** level of theory; (ii) the substituent-dependent steric and stereoelectronic effects on the bias of the two-state N reversible S equilibrium in nucleosides can also be predicted from the ab initio calculations with sufficiently large basis functions, and (iii) the necessity of mimicking the solvation behaviour of the experimental NMR measurement condition in the ab initio calculations of biomolecules is also emphasized.     

Application of statistical potentials to protein structure refinement from low resolution ab initio models

Recently ab initio protein structure prediction methods have advanced sufficiently so that they often assemble the correct low resolution structure of the protein. To enhance the speed of conformational search, many ab initio prediction programs adopt a reduced protein representation. However, for drug design purposes, better quality structures are probably needed. To achieve this refinement, it is natural to use a more detailed heavy atom representation. Here, as opposed to costly implicit or explicit solvent molecular dynamics simulations, knowledge-based heavy atom pair potentials were employed. By way of illustration, we tried to improve the quality of the predicted structures obtained from the ab initio prediction program TOUCHSTONE by three methods: local constraint refinement, reduced predicted tertiary contact refinement, and statistical pair potential guided molecular dynamics. Sixty-seven predicted structures from 30 small proteins (less than 150 residues in length) representing different structural classes (alpha, beta, alpha;/beta) were examined. In 33 cases, the root mean square deviation (RMSD) from native structures improved by more than 0.3 A; in 19 cases, the improvement was more than 0.5 A, and sometimes as large as 1 A. In only seven (four) cases did the refinement procedure increase the RMSD by more than 0.3 (0.5) A. For the remaining structures, the refinement procedures changed the structures by less than 0.3 A. While modest, the performance of the current refinement methods is better than the published refinement results obtained using standard molecular dynamics.     

Ab initio calculations for the optical rotations of conformationally flexible molecules: a case study on six-, seven-, and eight-membered fluorinated cycloalkanol esters

Based on the time-dependent density functional response theory, an approach for the prediction of optical rotations of enantiomers of conformationally flexible molecules was developed. The method was applied successfully for the determination of the absolute configuration of trans-2-fluorocycloalkanol acetates with different ring sizes. The largest deviations between experimental and theoretical [alpha](D) values are 10 deg x [dm x (g/cc)](-1) (about 20% error). These theoretical results suggest that the optical rotation in these molecules is dominated by the local (1R;2R) configuration of the two substituents and that different ring and even axial/equatorial orientations play a less important role.     

A fractional charge model for empirical calculations of peptide-water interactions.

The properties of an empirical model of interaction between a water molecule and polar groups of peptides or small peptides are explored. The H2O molecule is represented by a four-point charges distribution. In electron donor groups, a point charge is located on the axis of the lone pairs orbitals in order to introduce some directionality in hydrogen bonds. The effective potential is approximated by the sum of the coulombic interactions between point charges distribution and of a 6--12 atom-atom potential. The coefficients of this last potential are first adjusted by simulating the geometry of the water dimer. Equilibrium configurations of associated polar molecules and H2O predicted by the model are found to be in good agreement with those resulting from more sophisticated ab initio SCF calculations. Interactions between H2O and the side-chains of the cyclic dipeptide C(L-Thr-L-His) are then calculated. It is shown that internal bridging by water is an essential effect of the solvent. The experimental position of the H2O molecule is reproduced, stability of which depends also on intermolecular interactions.     

A theoretical investigation of the intercalative binding of 7-H pyrido[4.3C]carbazole chromophore into a d(CpG)2 minihelix

Theoretical computations are performed of the intercalative binding to a model d(CpG)2 minihelix of 7-H pyrido[4.3C]carbazole, the precursor of the antitumor bisintercalating drug ditercalinium. The conformations of the intercalation site are generated by the AGNAS procedure (algorithm to generate nucleic acid structures) of Miller and co-workers. The ligand-nucleotide interactions and the nucleotide conformational energies are computed with the SIBFA procedures (sum of interactions between fragments ab initio computed), which use formulas of empirical origin that reproduce ab initio SCF (self-consistent field) computations. Among the candidate intercalation sites most favored energetically, one has a pattern of conformational angles related to the one determined crystallographically by Sobell et al. in a series of x-ray structural studies of small intercalator-dinucleotide monophosphate complexes. Optimal values of the unwinding angle, found in the range of -12 degrees to -14 degrees, are consistent with available experimental data on DNA.     

Synthesis and density functional theoretical study of steroidal spiro-triazolidinone

The reaction of 3beta-chloro-5alpha-cholestan-6-one semicarbazone 1 with hydrogen peroxide at 0 degrees C gives 3beta-chloro-5alpha-cholestan-6-spiro-1',2',4'-triazolidine-3'-one 2 as a product. The structural assignment of the product was confirmed on the basis of its elemental, analytical and spectral data. The ab initio calculations were performed by using density functional theory (DFT) at B3LYP/6-31G* basis set in order to describe a free radical reaction mechanism. The reaction proceeds through two radical intermediates formation. The mechanism of the reaction was explained by using frontier molecular orbital (FMO), spin electronic density map, encoded electrostatic potential map and atomic charges. It was found that the localization of frontier orbitals and the flow of atomic charges of all the calculated structures support the present reaction mechanism. The molecular properties like total energy, dipole moment and hardness of each optimized structure, were also explained. Stability of all the optimized structures in this study was supported by their respective fundamental frequencies and energy minima.     

Odor distinctiveness between enantiomers of linalool: difference in perception and responses elicited by sensory test and forehead surface potential wave measurement

The effects on humans of inhalation of optically active linalools were examined in terms of sensory tests and portable forehead surface electroencephalographic (IBVA-EEG) measurements in order to assess their odor distinctiveness by chiral isomers. (R)-(-)-Linalools with specific rotation of [alpha](D) = -15.1 degrees were isolated by repeated flash column chromatography from lavender oil, while (S)-(+)-linalools with [alpha](D) = +17.4 degrees and (RS)-(+/-)-linalools with [alpha](D) = 0 degrees and content of (R)-form 50.9% and (S)-form 49.1% were obtained from coriander oil and commercial linalool, respectively, by using the same method. With the use of an inhalator, each was administered to subjects both before and after 10 min of work. It was found that administration after work evoked different subjective impressions when compared with that before work depending on the configuration of the isomers and the type of work employed. For instance, inhalation of (R)-(-)-linalool after hearing environmental sounds not only produced a much more favorable impression in the sensory test but was also accompanied by a greater decrease in beta waves after work in comparison with that before work. This is in contrast to the case of mental work, which resulted in a tendency for agitation accompanied by an increase in beta waves. These findings led us to conclude that enantiomeric stereospecificity of linalool evoked different odor perception and responses not only with chiral dependence but also with task dependence. In addition, in comparing these sensory profiling features and IBVA-EEG tendencies between hearing environmental sound and mental work, a tendency was observed for (R)-(-)-linalool to coincide with (RS)-(+/-)-linalool but not with (S)-(+)-linalool.     

The anaerobic ribonucleotide reductase from Escherichia coli. The small protein is an activating enzyme containing a [4fe-4s](2+) center.

For deoxyribonucleotide synthesis during anaerobic growth, Escherichia coli cells depend on an oxygen-sensitive class III ribonucleotide reductase. The enzyme system consists of two proteins: protein alpha, on which ribonucleotides bind and are reduced, and protein beta, of which the function is to introduce a catalytically essential glycyl radical on protein alpha. Protein beta can assemble one [4Fe-4S] center per polypeptide enjoying both the [4Fe-4S](2+) and [4Fe-4S](1+) redox state, as shown by iron and sulfide analysis, M?ssbauer spectroscopy (delta = 0.43 mm.s(-1), DeltaE(Q) = 1.0 mm.s(-1), [4Fe-4S](2+)), and EPR spectroscopy (g = 2. 03 and 1.93, [4Fe-4S](1+)). This iron center is sensitive to oxygen and can decompose into stable [2Fe-2S](2+) centers during exposure to air. This degraded form is nevertheless active, albeit to a lesser extent because of the conversion of the cluster into [4Fe-4S] forms during the strongly reductive conditions of the assay. Furthermore, protein beta has the potential to activate several molecules of protein alpha, suggesting that protein beta is an activating enzyme rather than a component of an alpha(2)beta(2) complex as previously claimed.     

The first enantioselective synthesis of the amavadin ligand and its complexation to vanadium

The ligand of the naturally occurring vanadium compound amavadin found in Amanita muscaria, (2S, 2'S)-N-hydroxyimino-2,2'-dipropionic acid (1), was synthesized stereoselectively in two steps with 43% overall yield. After complexation of this ligand to vanadyl acetate, amavadin was isolated in quantitative yield. Due to the chirality at vanadium amavadin consists of a mixture of delta and lambda diastereoisomers. Directly after its synthesis, the delta to lambda ratio of amavadin is 2.27 and it decreases to 0.80 after equilibrium has been reached. During this epimerization the optical rotation for V[(2S,2'S)-N-hydroxyimino-(2,2')-dipropionate]2 (=amavadin) changes from [alpha](D)25 = +36 degrees to +114.0 degrees (c = 0.5, H2O). For V[(2R,2'R)-N-hydroxyimino-(2,2')-dipropionate] the optical rotation changes from [alpha](D)25 = -36 degrees to -113.2 degrees (c = 0.5, H2O).     

An Investigation of Structural Stability and Internal Rotation in 3-Cyclopropenecarboxaldehyde and 3-Cyclopropenecarboxylic Acid Fluoride by ab initio Calculations

The structural stability and internal rotation in 3-cyclopropenecarboxaldehyde and 3-cyclo-propenecarboxylic acid fluoride were investigated by ab initio calculations with a 6-31G* atomic basis in the latter and a 6-311G* atomic basis set in the former case. For the sake of comparison also results obtained with a 3-21G basis are given in the paper. As expected, it turned out that this basis set is not large enough for three-membered rings. The calculations were carried out both at the Restricted Hartree-Fock (HF) and the second order Moller-Plesset (MP2) levels. The trans-form is predicted to be the lower energy conformer for both molecules. However, in case of the fluoride the two conformers have nearly the same energy. Full optimization was performed at the transition states and the asymmetric potential function for the CXO internal rotations was predicted for both molecules.     

Role of azaamino acid residue in beta-turn formation and stability in designed peptide.

The structural perturbation induced by C(alpha)-->N(alpha) exchange in azaamino acid-containing peptides was predicted by ab initio calculation of the 6-31G* and 3-21G* levels. The global energy-minimum conformations for model compounds, For-azaXaa-NH2 (Xaa=Gly, Ala, Leu) appeared to be the beta-turn motif with a dihedral angle of phi= +/- 90 degrees, psi=0 degrees. This suggests that incorporation of the azaXaa residue into the i+2 position of designed peptides could stabilize the beta-turn structure. The model azaLeu-containing peptide, Boc-Phe-azaLeu-Ala-OMe, which is predicted to adopt a beta-turn conformation was designed and synthesized in order to experimentally elucidate the role of the azaamino acid residue. Its structural preference in organic solvents was investigated using 1H NMR, molecular modelling and IR spectroscopy. The temperature coefficients of amide protons, the characteristic NOE patterns, the restrained molecular dynamics simulation and IR spectroscopy defined the dihedral angles [ (phi i+1, psi i+1) (phi i+2, psi i+2)] of the Phe-azaLeu fragment in the model peptide, Boc-Phe-azaLeu-Ala-OMe, as [(-59 degrees, 127 degrees) (107 degrees, -4 degrees)]. This solution conformation supports a betaII-turn structural preference in azaLeu-containing peptides as predicted by the quantum chemical calculation. Therefore, intercalation of the azaamino acid residue into the i+2 position in synthetic peptides is expected to provide a stable beta-turn formation, and this could be utilized in the design of new peptidomimetics adopting a beta-turn scaffold.