CNDO/2 molecular orbital calculations on the antifolate DAMP and some related species: structural geometries, ring distortions, change distributions and conformational characteristics

Geometry-optimized CNDO/2 molecular orbital calculations were carried out on 2, 4-diamino-5-(1-adamantyl 1)-6-methyl pyrimidine (DAMP), a potent inhibitor of mammalian dihydrofolate reductase which is now in clinical trials, and on its inactive 5-(1-naphthyl) analogue (DNMP-1). Crystallographic data show that DAMP (as the ethylsulfonate salt) has a severely distorted, N1 protonated, pyrimidine ring and has steric crowding of the 6-methyl and adamantyl hydrogens whereas DNMP-2 (as a methanol complex) has a planar, nonprotonated pyrimidine ring that is nearly perpendicular to the naphthalene ring. The CNDO/2 results largely reproduce the crystal structure geometry and show that the ring distortions in DAMP are initiated by steric conflicts between the adamantyl group and the 4- and 6-substituents on the ring. In DNMP-1, the non-interfering naphthyl ring induces little strain within the pyrimidine ring and the effect of protonation is negligible. Rotation about the bond joining the two ring groups is restricted in DAMP by a broad barrier of ca. 8.0 kcal mol-1, and no conformation was successful in relieving steric conflicts and hence reducing the ring distortions. In DNMP-1, rotation is less hindered overall with a broad region of accessible conformational space and a maximum barrier of ca. 7.2 kcal mol-1 for the coplanar conformation. The electronic charge distributions of DAMP and DNMP-1 are almost identical and protonation is preferred at N1 rather than at N3 by ca. 3.7 kcal mol-1 for both DAMP and DNMP-1. The calculations establish that the present methodology can be useful as a predictive tool with regard to the structure and conformational characteristics of these and related species.     

CNDO calculations on the conformational structure of acetylcholine

Molecular orbital theory in the CNDO framework has been used to calculate the torsional angles which lead to minimum energy conformations in acetylcholine. The calculated angles agree well with the experimental observations on acetylcholine and its derivatives. The results have been compared with the earlier predictions based on extended Hückel theory and van der Waal pairwise interactions.     

Quantitative structure-activity relationships of cardiotonic steroids using empirical molecular electrostatic potentials and semiempirical molecular orbital calculations

Empirical molecular electrostatic potentials and a rigid receptor H atom model are used to calculate differences in the interaction energy of cardiotonic steroids with the digitalis receptor. An attempt is made to map the receptor H binding sites for two different steroid conformations with respect to 17 beta side-chain orientation. The calculated interaction energies using single-crystal X-ray structure data indicate linear relationships with the Na+, K+-ATPase inhibitory activity. On the basis of these correlations, the activity of 8 so far pharmacologically not investigated steroids containing C = O in 17 beta substituents are estimated with the help of structural data determined by means of the semiempirical CNDO molecular orbital theory.     

All-valence-shell molecular orbital calculations on the chiroptical properties of substituted and unsubstituted 2,5-diketopiperazine structures

The chiroptical properties of L -3-methyl-2,5-diketopiperazine (L -alanylglycyl anhydride) are examined on a theoretical model in which the electronic wave functions are obtained from semi-empirical all-valence-shell molecular orbital calculations. The INDO molecular orbital model is used to perform SCF-MO calculations on the ground states of six conformation isomers of L -3-methyl-2,5-diketopiperazine and two chiral conformational isomers of unsubstituted 2,5-diketopiperazine. Excited-state wave functions are constructed in the virtual orbital-configuration interaction approximation. The rotatory strengths, dipole strengths, oscillator strengths, and dissymmetry factors of the first eight singlet–singlet transitions for each of the eight structures are calculated and reported. Additionally, ground-state dipole moments, net atomic charges, and the first four ionization potentials (calculated according to Koopman's theorem) are computed for each structure. The signs and the magnitudes of the rotatory strengths are found to be extremely sensitive to the conformation of the piperazine ring as well as to methyl substitution at the α carbon of the ring. Spectra–structure relationships based on the calculations reported here are discussed, and the available experimental CD data on dissymmetric 2,5-diketopiperazine are examined in terms of our theoretical results.     

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.     

Conformations and interactions of excited states. II. Polystyrene, polypeptides, and proteins

Previous fluorescence and phosphorescence studies of aromatic model compounds have been extended to polymers: “atactic” and isotactic polystyrene, seven aromatic poly-(amino acids), and two proteins. We have confirmed previous observations that both forms of polystyrene exhibit strong excimer fluorescence emission at room temperature but not at 77°K. Of the poly(amino acids) (all observed in helix-supporting solvents), poly-L -phenylalanine, poly(α-benzyl-L -aspartic acid), and poly-1-benzyl-L -histidine likewise show excimer emission at room temperature but not at 77°K., while poly-L -tyrosine, poly-L -tryptophan, poly(γ-benzyl-L -glutamic acid), and poly-S-benzyl-L -cysteine exhibit no excimer emission at either temperature. The aromatic residues of bovine serum albumin exhibit only “normal” fluorescence, but, lysozyme appears to be unique among proteins in showing excimer-like tryptophan emission in the native state; its luminescence becomes “normal” upon denaturation. It appears very probable that none of these polymers has a ground-state conformation in which the aromatic groups have face-to-face orientations appropriate for excimer interaction. It is concluded that at room temperature absorption of light can cause local “melting” of regular (usually helical) structures and thus, in some polymers, permit the attainment of a face-to-face arrangement of aromatic rings within the radiative lifetime of their excited singlet states. In certain other polymers (for reasons not clear at present), and in all polymers at 77°K., this does not occur. This concept is extended to provide a bettor basis for understanding the mechanism of formation of the photodimer of thy mine in irradiated DNA.     

Further consideration of flavin coenzyme biochemistry afforded by geometry-optimized molecular orbital calculations

Investigation of lumiflavin and several other isoalloxazine ring derivatives has been carried out by geometry-optimized molecular orbital calculations. The results have provided insight into the flexibility of the flavin cofactor in the reduced and oxidized states, the regions of the fused three-ring system that should play an important role in flavin electron transfers, and the structural and functional role of the xylene and heteroatomic portions of the flavin system. The significance of these results is reviewed in relation to the experimentally identified chemical and biochemical properties of the flavin nucleotide coenzymes.     

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 oligopeptides netropsin, distamycin and related compounds

The electronic structure of the antibiotics netropsin, distamycin A, and related compounds has been examined by various theoretical models. Calculations of both the Pariser-Parr-Pople (PPP) and the semiempirical CNDO/S types can account for the absorption spectrum of netropsin and distamycin A. The CD spectrum has been calculated for the conformation of netropsin found in the crystal structure of a netropsin/DNA dodecamer. Not all the CD spectral features can be attributed entirely to the chiral conformation of netropsin, indicating that there are significant interactions between netropsin and DNA. A CD calculation was also performed for distamycin A in a similar conformation. An examination of the charge-density maps of the excited states suggests that there is substantial charge transfer from the pyrrole ring to either of the adjacent peptide linkages in these systems. At higher energies, even longer distance charge transfer can be observed. Similar behavior was seen in the monomers pyrrole-2-carboxamide and 3-(formylamino)pyrrole.     

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.     

Cyclic oxyphosphoranes as model intermediates during splicing and cleavage of RNA: ab initio molecular orbital calculations on the conformational analysis.

Ab initio molecular orbital calculations have been carried out on hydrated adducts of methyl ethylene phosphate as a model intermediate during cleavage of RNA. Upon rotating the apical methoxyl group two kinds of stable conformers and two kinds of rotational transition states are located, the most stable conformation being gs-G where the dihedral angle between the apical methyl group and the basal ring oxygen is calculated to be 76 degrees. In this gs-G conformation one of the lone pairs on the apical oxygen is oriented antiperiplanar to the basal ring ester bond. The torsional energy required to rotate the methyl group about the phosphorus-apical oxygen bond leading to ts-C conformation, where the methyl group is eclipsed with the ring oxygen, is calculated to be 5.2 kcal/mol. Judging from the published substrate's coordinates in the RNase environment, the expected pentacoordinate-intermediate/transition state during the cleavage of RNA appears to be, in fact, the most stable gs-G conformation.     

Studying excited states of proteins by NMR spectroscopy.

Protein structure is inherently dynamic, with function often predicated on excursions from low to higher energy conformations. For example, X-ray studies of a cavity mutant of T4 lysozyme, L99A, show that the cavity is sterically inaccessible to ligand, yet the protein is able to bind substituted benzenes rapidly. We have used novel relaxation dispersion NMR techniques to kinetically and thermodynamically characterize a transition between a highly populated (97%, 25 degrees C) ground state conformation and an excited state that is 2.0 kcal mol(-1) higher in free energy. A temperature-dependent study of the rates of interconversion between ground and excited states allows the separation of the free energy change into enthalpic (Delta H = 7.1 kcal mol(-1)) and entropic (T Delta S = 5.1 kcal mol(-1), 25 degrees C) components. The residues involved cluster about the cavity, providing evidence that the excited state facilitates ligand entry.     

Complexes of vitamin B6. XVII. Crystal structure and molecular orbital calculations of the dichloro-bis-pyridoxol palladium(II) complex

The structure of dichloro-bis-pyridoxol palladium(II) complex [PdCl₂(C₈H₁₁O₃N)₂] has been determined from three dimensional X-ray data collection. The complex crystallizes in the monoclinic space group P2₁/c with Z=2 and cell dimensions a=5.265(3), b=17.250(6), c=10.253(6) Å, β= 95.40(2)°. The structure was refined to a final R factor of 0.060 for 1813 reflections with F ⩾ 3σ(F). The palladium atom lies in a symmetry center of inversion in a square plane coordinated to two chlorine atoms and two pyridine nitrogen atoms. Charge distributions and bond order matrix calculated from ARCANA-MO are given.     

Halogenated 2,5-pyrrolidinediones: synthesis, bacterial mutagenicity in Ames tester strain TA-100 and semi-empirical molecular orbital calculations

The chloroimide 3,3-dichloro-4-(dichloromethylene)-2,5-pyrrolidinedione, a tetrachloroitaconimide, is the principal mutagen produced by chlorination of simulated poultry chiller water. It is the second most potent mutagenic disinfection by-product of chlorination ever reported. Six of seven new synthetic analogs of this compound are direct-acting mutagens in Ames tester strain TA-100. Computed energies of the lowest unoccupied molecular orbital (E_LUMO) and of the radical anion stability (ΔH_f^rad−ΔH_f) from MNDO-PM3 for the chloroimides show a quantitative correlation with the Ames TA-100 bacterial mutagenicity values. The molar mutagenicities of these direct acting mutagenic imides having an exocyclic double bond fit the same linear correlation (ln M_m vs. E_LUMO; ln M_m vs. ΔH_f^rad−ΔH_f) as the chlorinated 2(5H)-furanones, including the potent mutagen MX, 3-chloro-4-(dichloro-methyl)-5-hydroxy-2(5H)-furanone, a by-product of water chlorination and paper bleaching with chlorine. Mutagenicity data for related haloimides having endocyclic double bonds are also given. For the same number of chlorine atoms, the imides with endocyclic double bonds have significantly higher Ames mutagenicity compared to their structural analogs with exocyclic double bonds, but do not follow the same E_LUMO or ΔH_f^rad−ΔH_f correlation as the exocyclic chloroimides and the chlorinated 2(5H)-furanones.     

Halogenated 2,5-pyrrolidinediones: synthesis, bacterial mutagenicity in Ames tester strain TA-100 and semi-empirical molecular orbital calculations

The chloroimide 3,3-dichloro-4-(dichloromethylene)-2,5-pyrrolidinedione, a tetrachloroitaconimide, is the principal mutagen produced by chlorination of simulated poultry chiller water. It is the second most potent mutagenic disinfection by-product of chlorination ever reported. Six of seven new synthetic analogs of this compound are direct-acting mutagens in Ames tester strain TA-100. Computed energies of the lowest unoccupied molecular orbital (E(LUMO)) and of the radical anion stability (DeltaH(f)(rad)-DeltaH(f)) from MNDO-PM3 for the chloroimides show a quantitative correlation with the Ames TA-100 bacterial mutagenicity values. The molar mutagenicities of these direct acting mutagenic imides having an exocyclic double bond fit the same linear correlation (lnM(m) vs. E(LUMO); lnM(m) vs. DeltaH(f)(rad)--DeltaH(f)) as the chlorinated 2(5H)-furanones, including the potent mutagen MX, 3-chloro-4-(dichloro-methyl)-5-hydroxy-2(5H)-furanone, a by-product of water chlorination and paper bleaching with chlorine. Mutagenicity data for related haloimides having endocyclic double bonds are also given. For the same number of chlorine atoms, the imides with endocyclic double bonds have significantly higher Ames mutagenicity compared to their structural analogs with exocyclic double bonds, but do not follow the same E(LUMO) or DeltaH(f)(rad)-DeltaH(f) correlation as the exocyclic chloroimides and the chlorinated 2(5H)-furanones.     

A molecular orbital selection approach for fast calculations of specific rotation with density functional theory

In this work, we describe a simple approach to select the most important molecular orbitals (MOs) to compute the optical rotation tensor through linear response (LR) Kohn-Sham density functional theory (KS-DFT). Taking advantage of the iterative nature of the algorithms commonly used to solve the LR equations, we select the MOs with contributions to the guess perturbed density that are larger than a certain threshold and solve the LR equations with the selected MOs only. We propose two criteria for the selection, and two definitions of the selection threshold. We then test the approach with two functionals (B3LYP and CAM-B3LYP) and two basis sets (aug-cc-pVDZ and aug-cc-pVTZ) on a set of 51 organic molecules with specific rotation spanning five orders of magnitude, 10⁰–10⁴ deg (dm⁻¹ (g/mL)⁻¹). We show that this approach indeed can provide very accurate values of specific rotation with estimated speedup that ranges from 2 to 8× with the most conservative selection criterion, and up to 20 to 30× with the intermediate criterion.