Ab initio Computational Modeling of Glyphosate Analogs: Conformational Perspective

A historical perspective on the application of conformational analysis to structure-based ligand design approach is presented. The application of isodensity molecular electrostatic potential surfaces with the conformational energy surfaces (CES) have allowed us to reach pertinent conclusions for aiding synthetic and biochemical studies. Here we illustrate such an application on the modeling of the potent analogs of an important, environmentally stringent herbicidal compound glyphosate by constructing conformational energy surfaces. The systems were modeled by substituting F, Cl, and NH— OH moiety to the position of pharmacophoric nitrogen center in glyphosate structure. All the calculations were thoroughly performed with ab initio MO theory at Hartree–Fock method using 3-21G(d) basis functions. On the basis of the results, we identified the bioactive conformations for N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate as (−38^∘, 77^∘), (−61^∘, 111^∘), and (−167^∘, −169^∘), respectively. Geometry optimization of certain selected conformations of these compounds using hybrid DFT method with 6–31+G(d) basis functions provides nearly equal values of φ and ψ. Moreover, the results indicate that the global minimum structures of N-fluoro and N-chloro analogs of glyphosate show cyclic conformation whereas the N-hydroxyamino-glyphosate global minimum structure shows spyrocyclic and zig-zag conformation. Also, the predicted bioactive conformation of N-hydroxyamino analog optimally overlaps with glyphosate backbone in EPSPS complex with 0.1 Å RMSD value. However, the other two compounds slightly deviate from the backbone of glyphosate with RMSD of 0.92 Å for N-fluoro-glyphosate and 0.83 Å for N-chloro-glyphosate. The linear N-hydroxyamino-glyphosate exhibits relatively more number of intermolecular hydrogen bond interactions as compared to the other two analogs. Further, comparison of CES of previously studied glyphosate analogs such as N-hydroxy-glyphosate (2.2 μM) and N-amino-glyphosate (0.61 μM) with the present systems reveals the order of activity as: N-hydroxyamino-glyphosate > N-fluoro-glyphosate > N-chloro-glyphosate based on CES flexibility. Also, the calculated heats of formation of N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate are −288, −209, and −288 kcal/mol, respectively, which clearly indicate that the N-hydroxyamino and N-fluoro analogs of glyphosate are thermodynamically more stable than N-amino-glyphosate (−278 kcal/mol).     

Dissociation constants of the ampholyte glycine in 50 mass % methanol-water from 5 to 55°C,with related thermodynamic quantities

The two thermodynamic dissociation constants of glycine at 11 temperatures from 5 to 55°C in 50 mass % methanol-water mixed solvent have been determined from precise emf measurements with hydrogen-silver bromide electrodes in cells without liquid junction. The first acidic dissociation constant (K ₁)for the process HG⁺H⁺+G^± is expressed as a function ofT(^oK) by the equation pK ₁ = 2043.5/T – 9.6504 + 0.019308T. At 25°C, pK ₁is 2.961 in the mixed solvent, as compared with 2.350 in water, with H°=1497 cal-mole^–1, G°=4038 cal-mole^–1, S°=–8.52 cal-°K^–1-mole^–1, and C _p ^o =–53 cal-°K^–1-mole^–1. The second acidic dissociation constant (K ₂)for the process G^±H⁺+G^– over the temperature range studied is given by the equation pK ₂ = 3627.1/T – 7.2371 + 0.015587T. At 25°C, pK ₂is 9.578 in MeOH–H₂O as compared with 9.780 in water, whereas H° is 10,257 cal-mole^–1, G° is 13,063 cal-mole^–1, S° is –9.41 cal-°K^–1-mole^–1, and C _p ^o is –43 cal-°K^–1-mole^–1. The protonated glycine becomes weaker in 50 mass % methanol-water, whereas the second dissociation process becomes stronger despite the lower dielectric constant of the mixed solvent (=56.3 at 25°C).     

Theoretical Study of Weakly Bound Dimers between Hydrogen Fluoride and Some Polar Molecules

Weakly bound linear and bent dimers, FH—X (where X = CO, OC, CNH, NCH, N₂O and ON₂), are investigated using the DFT B3LYP and ab initio MP2 methods with the same basis sets (6–311++G(3df,2pd)). The strengths of the H—C or H—N H‐bonds in dimers FH—CO, FH—CNH, and FH—N₂O are compared with those of the H—O or H—N H‐bonds in dimers FH—OC, FH—NCH, and FH—ON₂. The results obtained for the H‐bond distances, the elongation effect of the HF bond, the red shift of the HF stretching frequency, and the energy difference between the dimer and the charge transfer reveal that the H‐bonds of the first group of dimers are stronger than those of the second. The Gibbs energies calculated for the six dimer formations indicate that the weakly bound dimers are unstable at room temperature (T = 298 K) (FH—X's → FH + X's, ΔG < 0).     

Orbital correlation effects: The independent pair-potential approximation with application to the ground state and first ionized state of boron hydride

A new method is proposed for calculating correlation effects in atomic and molecular systems. The basis of the method is the formulation of a set of partial configuration expansions which yield directly variational orbital correlation corrections which are appropriately summed in order to obtain an estimate of the total correlation energy. This method is applied to the ground state of boron hydride and its cation at the equilibrium distance of BH. The results of the method are compared in detail with independent electron pair results and second order CI results. It is further shown that multiple substitutions are approximately accounted for in this method and the extent to which they are included is compared with other approximations. Finally, three methods of increasing accuracy, aimed at reducing the necessary computational effort, are given for determining the vertical ionization potential. The most economical method yields an IP of 9.70 eV or 0.03 eV less than the experimental IP. Completion of the basis is estimated to improve this value to 9.77 eV.     

Dipolar relaxations in an epoxy-amine system

Dipolar relaxations in a reactive epoxy-amine system based on diglycidyl ether of bisphenol A with 4,4^′-diaminodiphenylsulfone were studied with the Havriliak-Negami function. The system was cured isothermally at 140 °C using simultaneous kinetic and microdielectric studies.The relaxation time was calculated from the frequency f_max of the peak of the loss factor ε^′′ versus frequency f. A linear relation exists between the logarithm of the relaxation time τ and the glass transition temperature T_g. Then, logτ follows the Di Benedetto equation revisited by Pascault and Williams allowing the prediction of the relaxation time τ during cure.The unrelaxed permittivity at high frequency ε_u, the relaxed or static permittivity ε_s and the skewness parameter β were found independent on the conversion or the curing time. The distribution parameter α decreases as curing time t increases. The difficulty of orientation of dipoles in the electric field due to vitrification is responsible of these behaviours.     

Global optimization of univariate Lipschitz functions: II. New algorithms and computational comparison

We consider the following global optimization problems for a Lipschitz functionf implicitly defined on an interval [a, b]. Problem P: find a globally-optimal value off and a corresponding point; Problem Q: find a set of disjoint subintervals of [a, b] containing only points with a globally-optimal value and the union of which contains all globally optimal points. A two-phase algorithm is proposed for Problem P. In phase I, this algorithm obtains rapidly a solution which is often globally-optimal. Moreover, a sufficient condition onf for this to be the case is given. In phase II, the algorithm proves the-optimality of the solution obtained in phase I or finds a sequence of points of increasing value containing one with a globally-optimal value. The new algorithm is empirically compared (on twenty problems from the literature) with a best possible algorithm (for which the optimal value is assumed to be known), with a passive algorithm and with the algorithms of Evtushenko, Galperin, Shen and Zhu, Piyavskii, Timonov and Schoen. For small, the new algorithm requires only a few percent more function evaluations than the best possible one. An extended version of Piyavskii's algorithm is proposed for problem Q. A sufficient condition onf is given for the globally optimal points to be in one-to-one correspondance with the obtained intervals. This result is achieved for all twenty test problems.The research of the authors has been supported by AFOSR grants 0271 and 0066 to Rutgers University. Research of the second author has been also supported by NSERC grant GP0036426, FCAR grant 89EQ4144 and partially by AFOSR grant 0066. We thank Nicole Paradis for her help in drawing the figures.     

Time-resolved fluorescence analysis of the mobile flavin cofactor in p -hydroxybenzoate hydroxylase

Conformational heterogeneity of the FAD cofactor in p-hydroxybenzoate hydroxylase (PHBH) was investigated with time-resolved polarized flavin fluorescence. For binary enzyme/substrate (analogue) complexes of wild-type PHBH and Tyr222 mutants, crystallographic studies have revealed two distinct flavin conformations; the ‘in’ conformation with the isoalloxazine ring located in the active site, and the ‘out’ conformation with the isoalloxazine ring disposed towards the protein surface. Fluorescence-lifetime analysis of these complexes revealed similar lifetime distributions for the ‘in’ and ‘out’ conformations. The reason for this is twofold. First, the active site of PHBH contains various potential fluorescence-quenching sites close to the flavin. Fluorescence analysis of uncomplexed PHBH Y222V and Y222A showed that Tyr222 is responsible for picosecond fluorescence quenching free enzyme. In addition, other potential quenching sites, including a tryptophan and two tyrosines involved in substrate binding, are located nearby. Since the shortest distance between these quenching sites and the isoalloxazine ring differs only little on average, these aromatic residues are likely to contribute to fluorescence quenching. Second, the effect of flavin conformation on the fluorescence lifetime distribution is blurred by binding of the aromatic substrates: saturation with aromatic substrates induces highly efficient fluorescence quenching. The flavin conformation is therefore only reflected in the small relative contributions of the longer lifetimes.     

Ab initio studies of the protonation of CO,N2 and NO+: Calculation of the minimum energy reaction paths

Ab initio molecular orbital calculations employing a 4-31G basis set have been used to study the minimum energy paths for the formation of HCO⁺, COH⁺, and HCOH²⁺ from CO by protonation. The protonation of N₂ to give NNH⁺ and HNNH²⁺ and of NO⁺ to form HNO²⁺ and NOH²⁺ have also been investigated. All species formed have linear equilibrium geometries and the minimum energy path for approach of the proton is along the line-of-centers of the heavy atoms. Energy barriers to the formation of the various species are given, where appropriate, and changes in geometry, ordering of molecular orbitals and orbital occupancy are discussed.     

高空核电磁脉冲模拟波形的双指数函数拟合法

 许多标准和公开出版物中都用双指数函数描述高空核电磁脉冲典型波形。通过数值方法，研究了双指数函数一项重要的性质。根据该性质，详细讨论了高空核电磁脉冲模拟波形数值拟合中，双指数函数特征参数与脉冲峰值、前沿、后沿以及半宽等物理参数的关系，从而提出一种简单有效的脉冲参数计算方法。通过IEC标准中规定的高空核电磁脉冲参数的估计与一个实测高空核电磁脉冲模拟波形的数值拟合，验证了该方法的有效性和可靠性。该方法能够适应多种峰值、前沿和半宽的高宽核电磁脉冲模拟波形的数值拟合。