Quantum chemical studies on the conformational structure of bacterial peptidoglycan. III. CNDO and INDO calculations on the N-acetyl-giucosamine

CNDO and INDO semi-empirical all valence M.O. methods have been applied to predict the side group dihedral angles of N-acetyl glucosamine in order to compare the results of empirical, MNDO and PCILO studies already reported.The net atomic charges and dipole moments have also been computed. The present calculation suggests that the net atomic charges remain almost constant for the different conformers considered.The CNDO, INDO and PCILO methods predict nearly the same orientations for the side groups. Moreover, the quantum chemical methods suggest significant improvements over the empirical results although, in general, similar conformational features are observed. However, the MNDO results for some of the side groups are different from the ones obtained by all the above methods.     

Quantum chemical studies on the conformational structure of bacterial peptidoglycan. I. MNDO calculations on the glycan moiety

Semi-empirical quantum chemical calculations at MNDO level of approximations have been carried out on the monosaccharide and disaccharide moiety of bacterial peptidoglycan to determine the energetically favoured conformation of their side groups and the relative orientations of sugar rings. The results have been compared with those obtained from empirical energy calculations. The MNDO results have also been discussed with available experimental data and suggest that a chitin-like structure is not favoured for the glycan moiety of peptidoglycan.     

Molecular orbital calculations on the conformation of polypeptides and proteins. 8. The conformational energy maps and stereochemical rotational states of the asparaginyl, glutaminyl aspartyl and glutamyl residues

Quantum-mechanical calculations on the conformational energy map and stereo-chemical rotational states of aminoacid residues by the PCILO method are extended to the asparaginyl, glutaminyl, aspartyl and glutamyl residues in their neutral form. One of the most outstanding features of the results is the occurrence of the global minimum (or of one of a few equivalent global minima) in the region of the left handed α-helix for the first three of the above mentioned residues. The results of the calculations are compared with experimental data from eight, globular proteins which confirm that these residues may exist, in fact, in this conformation. They also enable to understand the experimentally observed possibility of helix reversal in esters of poly-L -aspartic acid as a function of substitutions in the side chain.     

Molecular orbital calculations on the conformation of polypeptides and proteins. V. Conformational energy maps and stereochemical rotational states of aliphatic residues

The quantum-mechanical calculations by the PCILO method on the conformation of amino acid residues of proteins have been extended to the valyl, leucyl, and isoleucyl residues. In distinction to the earlier “empirical” computations, the quantum-mechanical results indicate very similar energy contours for the stable conformations of the three residues. Their general outline is also similar to that of the alanyl residue, although reduced by about 25%. Contrary to the “empirical” computations, the present results predict that the region corresponding to the α-helix should be one of great stability for the three residues and in particular for the valyl residue. The quantum-mechanical results are in excellent agreement with the experimental conformations of the aliphatic residues in lysozyme and myoglobin. Their prediction as to the ready availability of the valyl residue in the α-helical conformation agrees moreover with Ptitsyn's statistical evaluation of the participation of this residue in the inner turns of the helical regions in six globular proteins. The maximum conformational space allowed for the aliphatic residues is somewhat smaller than that allowed for the aromatic ones, while the minimum conformational space (region of stability common to all the residues) is similar in both groups.     

Molecular orbital calculations on the conformation of polypeptides and proteins. II. Conformational energy maps and stereochemical rotational states of aromatic residues

Our previous quantum-mechanical calculations, by an all-valence-electrons method (PCILO) taking into account simultaneously the σ and π electrons of the system, on the conformation energy maps of the glycyl and alanyl residues are extended to the evaluation of these maps and of the stereochemical rotational states of the aromatic residues, phenylalanyl, tyrosyl, histidyl, and tryptophanyl in dipeptides. Calculations on model compounds are used for the predetermination of the side-chain rotational angles χ₁ and χ₂ which are then used as selected parameters for the evaluation of the conformational energy maps as function of the backbone rotational angles Φ and ψ. The theory predicts that the most stable conformation for these aromatic residues should occur in the same region, around Φ = 200, ψ = 140°, in which it was predicted to occur for the glycyl and alanyl residues and which was completely overlooked by most of the previous “empirical” computations. Recent experimental work by a group of Russian authors using NMR and infrared techniques seems to confirm the theoretical result for the alanyl and phenylalanyl residues. The paper indicates also the secondary local minima which appear for the different residues. The theoretically allowed general conformational area for the four aromatic residues, within the reasonable value of 5 kcal/mole above the deepest minimum, is somewhat larger than the similar area allowed by the “hard sphere” empirical calculations. Practically all available representative experimental points from the study of small molecules and of the proteins lysozyme and myoglobin fall within the allowed area, the agreement being better with the results of the quantum mechanical calculations than with those of the “hard sphere” approximation. The values of the side-chain rotational angles χ₁ and χ₂ and of their allowed combinations agree less satisfactorily with experiment, the experimentally observed combinations being more varied than the theoretically allowed ones. These last ones having, however, been predetermined on studies with model compounds, this situation is not astonishing. It is proposed to refine these results by a minimization with respect to the four parameters Φ, ψ, χ₁, and χ₂ involved.     

A molecular orbital study on the conformation of enniatin B

Molecular orbital calculations using the PCILO method are performed on the conformation of the symmetrical form of enniatin B. The values of the Φ and ψ angles found for the preferred conformation agree closely with the results of X-ray study of the K⁺ complex of enniatin B.     

Influence of conformation on the fluorescence of tryptophan-containing peptides

Conformational-energy calculations of the zwitterionic forms of Trp, Gly-Trp, Pro-Trp, Phe-Trp, Trp-Gly, Trp-Phe, Trp-Trp, and Trp-Gly-Gly were done using an empirical energy program for peptides (ECEPP). The resulting low-energy conformations were analyzed for the presence of hydrogen bonds, the distances between carbonyl groups and the indole ring, the distances between the N-terminal amino group and the indole ring, the dihedral angle between the planes containing carbonyl groups and the indole ring, and for dipeptides with two aromatic side chains, the dihedral angle and distance between the planes of the aromatic rings. This information was correlated with literature data from x-ray crystallographic studies, fluorescence lifetime studies, and quantum-yield experiments; proposed models of intramolecular quenching are discussed in light of the peptide conformations.     

Quantum mechanical conformational analysis of heterocyclic analogues of norephedrine

Studies on the conformation of several structural analogues of norephedrine, thiophene, carbazole and furan, were carried out using the differential PCILO method. The erythro-forms of these compounds possess minima on the conformation map corresponding to a gauche conformation with synclinal H-atoms. This result is in good agreement with the proton-proton coupling constants found in previous NMR-studies. ¹H-NMR-studies suggest for the threo-isomers of the studied molecules an equilibrium between the trans- and gache-conformations of the ethanolamine chain. Present calculations agree fairly well with this result. All the studied molecules possess conformational minima corresponding to the folded form of the side chain believed responsible for the physiological activity of norephedrine. The distances between ‘N’ and ‘O’ atoms in this preferred conformation correspond to the model proposed by Kier and Pullman for α-adrenergic receptors.     

Modeling, design, chiral aspects and role of para-substituents in aryloxypropranolamine based beta-blockers.

The conformation of the beta-blockers viz. metoprolol, atenolol, bisoprolol, betaxolol and celiprolol has been investigated using Perturbative Configuration Interaction of Localized Orbitals (PCILO) method. The conformational energy maps have been constructed for both the enantiomers (R and S) by rotating the molecule from the para-substituent end. The aryloxypropranolamine moiety adopts the same conformation for all antagonists. The graphical view of R- and S- form of these antagonists in the lowest energy conformation reveals that it is only in the S- form of beta-blockers, all the three functionalities--aromatic moiety, amino and beta-hydroxyl groups are available for interaction with beta-adrenoceptors. The para-substituents of the beta-blockers adopt a conformation which is perpendicular to the aryloxy moiety resulting in an L-shaped structure. The beta-antagonists possibly partition into the lipid bilayer through the para-substituents and the aryloxypropranolamine moiety containing the functionalities, thus, lies parallel to the plane of lipid bilayer for interaction with beta-adrenoceptors. Superimposition of S-bisoprolol in lowest energy conformation with the 3rd putative transmembranous segment of the beta-adrenoceptors reveals that the aromatic moiety, amino and beta-hydroxyl groups of antagonists are involved in interaction with the side chains of Trp-109, Asp-113 and Thr-110 respectively. This has been further substantiated by the interaction studies on the model systems.     

THE PROBLEM OF THE FUTURE WORLD: W.E.B. DU BOIS AND THE RACE CONCEPT AT MIDCENTURY

Most studies of police–minority relations in America focus on blacks, usually in comparison with whites. This pattern is particularly puzzling in light of the growing population of Hispanic Americans throughout the US, now outnumbering blacks and consisting of the majority in some major cities. Aside from the need for more empirical research on the policing of Hispanics per se, comparing Hispanics’ relations with the police to other racial and ethnic groups offers some important insights into both the dimensions that are shared across groups and those that are distinctive to Hispanics. This article critically evaluates the small body of empirical research literature on this topic – highlighting both deficiencies in this literature as well as suggestive findings – and concludes by identifying a set of issues that should be addressed in future studies. The available evidence largely supports a racial-hierarchy perspective with regard to the policing of different racial and ethnic groups in the US.     

Molecular orbital studies on the structure of nucleoside analogs. I. Conformation of 8-azapurine nucleosides

PCILO (perturbative configuration interaction using localized orbitals) computations have been carried out for the conformational properties of 8-azapurine nucleosides. The results indicate an anti conformation for Xcn and a gg conformation for phiC(4')-C(5') for C(2')-endo 8-aza analogs compared to the syn and gg conformation for the corresponding purine nucleosides. For C(3')-endo sugar puckering, both molecules prefer the syn conformation due to intramolecular hydrogen bonding between O(5')-H of the sugar and N(3) of the base, the preference being more profound in 8-aza analogs. The crystallographic conformation 8-azaadenosine has been attributed to crystal forces. The available NMR data on 8-azapurine nucleosides are in agreement with the PCILO predictions.     

Bond order weighted graphs in molecules as structure-property indices

A new topological index is defined. This index can be used in the presence of multiple bonds, considering molecules as weighted graphs, where the elements of the edge set are substituted by bond orders between the connected atoms in the molecule calculated by both empirical and semi-empirical quantum mechanical methods. Good correlations are found between the boiling points of alkenes and the proposed index,which permits one to differentiate between alkenes with different branching, position of the double bonds and geometrical disposition of the groups. Indexes calculated using two different methods (EHT and MNDO without geometry optimization) do not show appreciable differences in regression parameters. Deviations of predicted values in cases where methyl groups are linked to double bonds can be treated with a two-variable regression.     

Studies of the influence of chloro-substituent sites and conformational energy in polychlorinated biphenyls on uroporphyrin formation in chick-embryo liver cell cultures.

Treatment of cultured chick-embryo liver cells with polychlorinated biphenyls (PCB) results in decreased uroporphyrinogen decarboxylase activity and increased uroporphyrin accumulation. In the present study we examined the effect of the chloro- or bromo-substituent sites in biphenyls (BP) on uroporphyrin accumulation in cultured hepatocytes and the three-dimensional structure of these congeners determined by molecular orbital calculations using a MNDO ('modified neglect of diatomic overlap') method. Among 20 congeners examined, those which were effective in stimulating porphyrin accumulation contained at least two Cl or Br atoms at the lateral adjacent positions in each phenyl ring, e.g. 3,4,3',4'-tetrachloro-, 2,4,3',4'-tetrachloro-, 3,4,5,3',4',5'-hexachloro- and 3,4,5,3',4',5'-hexabromobiphenyl, whereas those which contained less than two halogen atoms or more than three halogen atoms in each phenyl ring or those which contained halogen atoms at 2,2'-positions were not effective. On the basis of the conformational energy (delta E, difference from the most stable conformational energy), which is calculated as a function of the dihedral angle (theta) between the two phenyl rings, biphenyl congeners can be classified into four groups with different conformations. The conformation of active PCB was relatively flexible, whereas inactive species had a rigidly angulated conformation. Furthermore, the calculated probability of the conformation distribution for each congener indicated that the probability of co-planarity was higher for active biphenyls than for inactive congeners. These structural characteristics suggest the significance of both the chloro-substituent sites and the conformational energy reflecting the phenyl-ring twist angles in determining the inhibitory effect of PCB on uroporphyrinogen decarboxylase activity.     

Conformational analysis of cytokinins and analogs

The conformational energy surfaces of 12 active cytokinins and analogs are studied with the aid of PCILO quantum mechanical calculations. The resulting conformational energy maps indicate that cytokinin activity is associated with the ability of the above molecules to attain a specific conformation, presumably related to their conformation at the active site of cytokinin receptor(s). The calculations locate the conformational energy minima and describe the flexibility of the studied molecules in terms of conformational barriers and transition paths. An approximate relation is found between cytokinin activity and the values of energy barriers to transitions between certain local minima. According to this relation, active compounds should have rotational barriers within 4–12 kcal/mol, besides the known hitherto constitutional requirements for high physiological activity.     

Molecular orbital studies on nucleoside analogs. II. Conformation of 6-azapyrimidine nucleosides.

PCILO (Perturbative Configuration Interaction using Localised Orbitals) computations have been carried out for three 6-azapyrimidine nucleosides, 6-azauridine, 6-azacytidine and 6-azathymidine, for both C(2')-endo and C(3')-endo pucker of the sugar ring. The results indicate a syn (chiCN=180 degrees) conformation followed by chiCN=90 degrees and gg conformation for C(3')-endo 6-aza analogs as compareed to the anti (chiCN=0 degrees) and gg conformation preferred by the corresponding pyrimidine nucleosides. For C(2')-endo sugar geometry, 6-azauridine and 6-azacytidine prefer, respectively, chiCN=0 degrees (anti) and phi C(4')-C(5')=60 degrees C (gg) and chiCN-240 degrees (syn) and phi C(4')-C(5')=120 degrees. The corresponding nucleosides, uridine and cytidine, show a preference for syn (chiCN=240 degrees) and gg and anti(chiCN=0 degrees) and gg , respectively. The X-ray crystallographic conformations of 6-azauridine and 6-azacytidine have been attributed to intermolecular hydrogen bonding and crystal packing forces. The results of PMR, CD and ORD studies on 6-azauridine and 6-azacytidine in aqueous solutions are in agreement with the PCILO predictions.     

Hydration of peptides. II. Determination of the preferred sites of interactions of a cyclic dipeptide with water

As a first step in the determination of the hydration scheme of small peptides, the hydration sites of the cyclic dipeptide c(l-Thr-l-His) have been determined by two empirical potential treatments. In the first approach the energy is calculated by using the “Caillet-Claverie's” potentials, including electrostatic, dispersion-repulsion and polarization contributions. In the second approach (EMPWI method), the energy is calculated by simplified treatment, taking into account the electrostatic interactions of a suitable charge distribution and the dispersion-repulsion contributions. In this study, only the crystalline conformation of the cyclic dipeptide is considered. The hydration sites determined can be classified in three groups: (a) bridging sites, in which water interacts with both side chains, (b) bridging sites in which water interacts with one side chain and the DKP ring, (c) individual sites in which water interacts only with one polar group. The agreement between the results obtained by the two calculations is sufficiently satisfactory. This allows us to use EMPWI potential for calculations of more complex systems.     

Solution behavior of methyl beta-xylobioside: conformational flexibility revealed by n.m.r. measurements and theoretical calculations

The conformations of methyl beta-xylobioside in solution have been determined by n.m.r. spectroscopy. Interglycosidic 3JC,H values and the chemical shifts of the 13C resonances were measured at various temperatures in the range 238-378 K for solutions in 1,4-dioxane, methanol, methyl sulfoxide, and water. The temperature and solvent dependencies of the data obtained suggest conformational flexibility. Quantum-chemical PCILO calculations, with evaluation of the solvent effects, and molecular mechanics calculations revealed the existence of 7 low-energy regions for which the geometries and energies were determined. The computed abundances of conformers and averaged J values accord with the experimental data.     

Quantum chemical studies on the conformational structure of nucleic acids. IV. Calculation of backbone structure by CNDO method

Quantum chemical calculations using the CNDO/2 method, have been carried out to determine the energetically favoured ranges of the torsional angles (φ′, ω′, ω, φ, ψ) which fix the conformational structure of nucleic acid backbone. The two dimensional isoenergy maps have been constructed in the (ω′, ω) and (φ, ψ) hyperspaces. The variation of total energy with respect to φ′ has also been studied. The results show that the non-bonding interactions play a major role in the conformational stability of nucleic acids and polynucleotides. The theoretical predictions show good correspondence with the experimental data (X-ray and ¹³C NMR) as well as the other reported theoretical calculations (EHT, PCILO and classical potential functions). The most favoured structure has the conformational angles close to 240, 290, 290, 180 and 60° and these values lead to a helical structure with a pitch of 34 Å and about ten nucleotide units per turn of the helix. The proposed models of Watson &; Crick, DNA-B and DNA-C lie in high energy regions.     

The influence of amino acid protonation states on molecular dynamics simulations of the bacterial porin OmpF

Several groups, including our own, have found molecular dynamics (MD) calculations to result in the size of the pore of an outer membrane bacterial porin, OmpF, to be reduced relative to its size in the x-ray crystal structure. At the narrowest portion of its pore, loop L3 was found to move toward the opposite face of the pore, resulting in decreasing the cross-section area by a factor of approximately 2. In an earlier work, we computed the protonation states of titratable residues for this system and obtained values different from those that had been used in previous MD simulations. Here, we show that MD simulations carried out with these recently computed protonation states accurately reproduce the cross-sectional area profile of the channel lumen in agreement with the x-ray structure. Our calculations include the investigation of the effect of assigning different protonation states to the one residue, D(127), whose protonation state could not be modeled in our earlier calculation. We found that both assumptions of charge states for D(127) reproduced the lumen size profile of the x-ray structure. We also found that the charged state of D(127) had a higher degree of hydration and it induced greater mobility of polar side chains in its vicinity, indicating that the apparent polarizability of the D(127) microenvironment is a function of the D(127) protonation state.     

Hydration of amino acid side chains: dependence on secondary structure.

Energy calculations have been used to study the hydration sites around the polar groups of serine, threonine and tyrosine side chains. These hydration sites depend not only on the hybridization of the polar group but also on the local secondary structure, the chi 1 side chain torsion angle and the position of the hydroxyl hydrogen atom. For tyrosine side chains, two solvent sites are found approximately in the plane of the ring. Even for serine and threonine side chains only two minimum energy sites are found in general of which one is in an expected position within hydrogen bonding of the hydroxyl hydrogen atom (unless this is blocked from interaction with solvent molecules by, for example, Oi-4 or Oi-3. The position of the second of these sites depends not only on the position of the hydroxyl oxygen but also on neighbouring main chain atoms to which it can also hydrogen bond. There is good agreement with the solvent distributions obtained from crystallographic data.