Using Hessian Updating To Increase the Efficiency of a Hessian Based Predictor-Corrector Reaction Path Following Method.

The reaction path is a key concept in the theoretical description of a chemical reaction. The intrinsic reaction coordinate is defined as the steepest descent path in mass-weighted Cartesian coordinates that connects the transition state to reactants and products on the potential energy surface. Recently, a new Hessian based predictor-corrector reaction path following algorithm was presented that is comparable to a fourth-order algorithm developed earlier. Although the method is very accurate, it is costly because second derivatives of the energy are required at each step. In this work, the efficiency of the method is greatly enhanced by employing Hessian updating. Three different updating schemes have been tested: Murtagh and Sargent, Powell-symmetric Broyden, and Bofill. Bofill's update performs the best and yields excellent speed-up.

Early transition metal complexes containing 1,2,4-triazolato and tetrazolato ligands: synthesis, structure, and molecular orbital studies.

Several early transition metal complexes bearing 1,2,4-triazolato and tetrazolato ligands have been prepared by reaction of the pyrazolato complexes Ti(tBu(2)pz)(4-x)Cl(x) (tBu(2)pz = 3,5-di-tert-butylpyrazolato; x = 1, 2) and M(tBu(2)pz)(5-x)Cl(x) (M = Nb, Ta: x = 2, 3) with the sodium or potassium salts derived from 1,2,4-triazoles and tetrazoles. The X-ray structure analysis of Ti(tBu(2)pz)(2)(Me(2)C(2)N(3))(2) shows eta(2)-coordination of the 1,2,4-triazolato ligands, while in Ti(tBu(2)pz)(3)(C(2)H(2)N(3)) and Nb(tBu(2)pz)(3)(Me(2)C(2)N(3))(2) the analogous groups are joined in a eta(1)-fashion in the solid-state structure. Solution NMR studies at different temperatures suggest transition states involving eta(2)-1,2,4-triazolato ligands for the complexes containing eta(1)-1,2,4-triazolato ligands in the solid state. X-ray crystal structures of analogous tetrazolato complexes Ti(tBu(2)pz)(3)(PhCN(4)) and Nb(tBu(2)pz)(3)(PhCN(4))(2) show eta(1)-coordination of the 2-nitrogen atoms of the tetrazolato ligands. Molecular orbital calculations have been carried out on several model titanium complexes and provide detailed insight into the bonding between early transition metal centers and 1,2,4-triazolato and tetrazolato ligands. The eta(2)-coordination mode of 1,2,4-triazolato and tetrazolato ligands is predicted to be more stable than the eta(1)-coordination mode by 13.8-5.2 kcal/mol.

Mechanism of ascorbic acid oxidation by cytochrome b(561).

The 1 equiv reaction between ascorbic acid and cytochrome b(561) is a good model for redox reactions between metalloproteins (electron carriers) and specific organic substrates (hydrogen-atom carriers). Diethyl pyrocarbonate inhibits the reaction of cytochrome b(561) with ascorbate by modifying a histidine residue in the ascorbate-binding site. Ferri/ferrocyanide can mediate reduction of DEPC-treated cytochrome b(561) by ascorbic acid, indicating that DEPC-inhibited cytochrome b(561) cannot accept electrons from a hydrogen-atom donor like ascorbate but can still accept electrons from an electron donor like ferrocyanide. Ascorbic acid reduces cytochrome b(561) with a K(m) of 1.0 +/- 0.2 mM and a V(max) of 4.1 +/- 0.8 s(-1) at pH 7.0. V(max)/K(m) decreases at low pH but is approximately constant at pH >7. The rate constant for oxidation of cytochrome b(561) by semidehydroascorbate decreases at high pH but is approximately constant at pH <7. This suggests that the active site must be unprotonated to react with ascorbate and protonated to react with semidehydroascorbate. Molecular modeling calculations show that hydrogen bonding between the 2-hydroxyl of ascorbate and imidazole stabilizes the ascorbate radical relative to the monoanion. These results are consistent with the following mechanism for ascorbate oxidation. (1) The ascorbate monoanion binds to an unprotonated site (histidine) on cytochrome b(561). (2) This complex donates an electron to reduce the heme. (3) The semidehydroascorbate anion dissociates from the cytochrome, leaving a proton associated with the binding site. (4) The binding site is deprotonated to complete the cycle. In this mechanism, an essential role of the cytochrome is to bind the ascorbate monoanion, which does not react by outer-sphere electron transfer in solution, and complex it in such a way that the complex acts as an electron donor. Thermodynamic considerations show that no steps in this process involve large changes in free energy, so the mechanism is reversible and capable of fulfilling the cytochrome's function of equilibrating ascorbate and semidehydroascorbate.

Fluorophore-labeled S-nitrosothiols.

A series of fluorophore-labeled S-nitrosothiols were synthesized, and their fluorescence enhancements upon removal of the nitroso (NO) group were evaluated either by transnitrosation or by photolysis. It was shown that, with a suitable alkyl linker, the fluorescence intensity of dansyl-labeled S-nitrosothiols could be enhanced up to 30-fold. The observed fluorescence enhancement was attributed to the intramolecular energy transfer from fluorophore to the SNO moiety. Ab initio density functional theory (DFT) calculations indicated that the "overlap" between the SNO moiety and the dansyl ring is favored because of their stabilizing interaction, which was in turn affected by both the length of the alkyl linker and the rigidity of the sulfonamide unit. In addition, one of the dansyl-labeled S-nitrosothiols was used to explore the kinetics of S-nitrosothiol/thiol transnitrosation and was evaluated as a fluorescence probe of S-nitrosothiol-bound NO transfer in human umbilical vein endothelial cells.

Insight into the complex and dynamic process of activation of matrix metalloproteinases.

Matrix metalloproteinases (MMPs) are important hydrolytic enzymes with profound physiological and pathological functions in living organisms. MMPs are produced in their inactive zymogenic forms, which are subsequently proteolytically activated in an elaborate set of events. The propeptide in the zymogen blocks the active site, with a cysteine side-chain thiolate from this propeptide achieving coordination with the catalytically important zinc ion in the active site. Molecular dynamics simulations, ab initio calculations, and wet chemistry experiments presented herein argue for the critical importance of a protonation event at the coordinated thiolate as a prerequisite for the departure of the propeptide from the active site. Furthermore, a catalytically important glutamate is shown to coordinate transiently to the active-site zinc ion to "mask" the positive potential of the zinc ion and lower the energy barrier for dissociation of the protonated cysteine side chain from the zinc ion. In addition, a subtle conformational change by the propeptide is needed in the course of zymogen activation. These elaborate processes take place in concert in the activation process of MMPs, and the insight into these processes presented herein sheds light on a highly regulated physiological process with profound consequences for eukaryotic organisms.

Inversion versus retention of configuration for nucleophilic substitution at vinylic carbon.

A high-level computational study using CCSD, CCSD(T), and G2(+) levels of theory has shown that unactivated vinyl substrates such as vinyl chloride would afford gas phase, single-step halide exchange by a pure in-plane sigma-approach of the nucleophile to the backside of the C--Cl sigma bond. Geometry optimization by CCSD/6-31+G* and CCSD(T)/6-31+G* confirms the earlier findings of Glukhovtsev, Pross, and Radom that the S(N)2 reaction of Cl(-) with unactivated vinyl chloride in the gas phase occurs by a sigma attack. Complexation of vinyl chloride with Na(+) does not alter this in-plane sigma preference. However, moderately activated dihaloethylenes such as 1-chloro-1-fluoroethylene undergo gas-phase S(N)2 attack by the accepted pi-route where the nucleophile approaches perpendicular to the plane of the C==C. In the latter case a single-step pi pathway is preferred for the Cl(-) + H(2)C==CFCl reaction. This is the first definitive example at a high level of theory where a single-step pi nucleophilic vinylic substitution is preferred over a multistep mechanism in the gas phase. The activation barriers for these gas-phase single-step sigma- and pi-processes involving both naked anions and Na(+) complexes are, however, prohibitively high. Solvation and the presence of a counterion must play a dominant role in nucleophilic vinylic substitution reactions that proceed so readily in the condensed phase. In solution, nucleophilic vinylic substitution reactions involving electron-withdrawing groups on the carbon--carbon double bond (e.g., -CN, -CHO, and -NO(2)) would almost certainly proceed via a free discrete carbanionic intermediate in accord with experiment.

A single transition state serves two mechanisms: an ab initio classical trajectory study of the electron transfer and substitution mechanisms in reactions of ketyl radical anions with alkyl halides.

Molecular dynamics has been used to investigate the reaction of a series of ketyl anion radicals and alkyl halides, CH2O(*)(-) + CH3X (X = F, Cl, Br) and NCCHO(*)(-) + CH3Cl. In addition to a floppy outer-sphere transition state which leads directly to ET products, there is a strongly bound transition state that yields both electron transfer (ET) and C-alkylated (SUB(C)) products. This common transition state has significant C-- C bonding and gives ET and SUB(C) products via a bifurcation on a single potential energy surface. Branching ratios have been estimated from ab initio classical trajectory calculations. The SUB(C) products are favored for transition states with short C--C bonds and ET for long C--C bonds. ET reactivity can be observed even at short distances of r(C)(-)(C) = ca. 2.4 A as in the transition state for the reaction NCCHO(*)(-) + CH3Cl. Therefore, the ET/SUB(C) reactivity is entangled over a significant range of the C--C distance. The mechanistic significance of the molecular dynamics study is discussed.

para-Substituted N-nitroso-N-oxybenzenamine ammonium salts: a new class of redox-sensitive nitric oxide releasing compounds.

N-Nitroso-N-oxybenzenamine ammonium salts with -OMe, -Me, -H, -F, -Cl, -CF3, and -SO2Me substituents at the para position of the phenyl ring constitute a new class of-redox sensitive nitric oxide (NO) releasing compounds. These compounds yield nitric oxide and the corresponding nitrosobenzene derivatives by a spontaneous dissociation mechanism after undergoing a one electron oxidation. Oxidation of these compounds can be achieved through chemical, electrochemical and enzymatic methods. It was observed electrochemically that the amount of NO generated was dependent on the substituent effect and the applied oxidation potential. Electron-withdrawing substituents increase the oxidation potential of the compound. A linear correlation was observed when the peak potentials for the oxidation were graphed versus the Hammett substituent constant. Density functional theory calculations were also performed on this series of compounds. The theoretical oxidation energies of the corresponding anions show a strong linear correlation with the experimental potentials. Furthermore, enzymatic oxidation using horseradish peroxidase showed a similar substituent effect. These results indicate that substitution at the para position of the phenyl ring has a profound effect on the stability, oxidation potential and enzymatic kinetic properties of the compounds. Thus para-substituted N-nitroso-N-oxybenzenamine salts comprise a new class of redox-sensitive nitric oxide releasing agents.

Structure-activity, theoretical, and X-ray studies on the intramolecular interactions in a series of novel histamine H2 receptor antagonists.

The furan ring of the histamine H2 receptor antagonist 3-amino-4-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl] thio]ethyl]amino]-1,2,5-thiadiazole 1-oxide (1a) was replaced by thiophene, pyridine, benzene, and pyrrole. The relative receptor affinities of these analogues were estimated by in vitro and in vivo techniques. A theoretical model for the stacking interaction, observed by single crystal X-ray analysis of 1a, was developed, and the ability to enter into this type of interaction was estimated. The X-ray analysis of the pyridine analogue of 1a revealed no intramolecular stacking interaction. The theoretical studies were evaluated in light of the observed receptor affinities, and the relevance of the solid-state geometry of 1a to the receptor-bound geometry was assessed. It is suggested that the stacked geometry found in the X-ray structure of 1a does not represent a conformation that is relevant to that bound at the histamine H2 receptor.

The relationship of the carcinogenic/mutagenic potential of arylamines to their singlet-triplet nitrenium ion energies.

Utilizing intermediate neglect of differential overlap (INDO) and ab initio methodology, trends in the energy differences between the singlet and triplet states for mono- and polycyclic aryl nitrenium ions have been estimated. Calculations reveal an empirical correlation between the energy separation of the singlet and triplet states of the nitrenium ion and the ability of the parent amine to behave as a carcinogen or mutagen. Non-carcinogenic/non-mutagenic arylamines were characterized by nitrenium ions whose singlet states were much less stable than the triplet. Carcinogenic/mutagenic amines were characterized by nitrenium ions whose singlet states were of similar or greater stability than the triplet. By examination of the charge density at key ring atoms of the singlet and triplet species, a rational approach to the stabilization of one species relative to the other has merged and forms the basis for prediction of genotoxicity in closely related structures. The application of this empirical correlation to the prediction of the carcinogenic/ mutagenic potential of arylamines is discussed.