Theoretical modeling of enzyme catalytic power: analysis of "cratic" and electrostatic factors in catechol O-methyltransferase

A comparative theoretical study of a bimolecular reaction in aqueous solution and catalyzed by the enzyme catechol O-methyltransferase (COMT) has been carried out by a combination of two hybrid QM/MM techniques: statistical simulation methods and internal energy minimizations. In contrast to previous studies by other workers, we have located and characterized transition structures for the reaction in the enzyme active site, in water and in a vacuum, and our potential of mean force calculations are based upon reaction coordinates obtained from features of the potential energy surfaces in the condensed media, not from the gas phase. The AM1/CHARMM calculated free energy of activation for the reaction of S-adenosyl methionine (SAM) with catecholate catalyzed by COMT is 15 kcal mol(-1) lower the AM1/TIP3P free-energy barrier for the reaction of the trimethylsulfonium cation with the catecholate anion in water at 300 K, in agreement with previous estimates. The thermodynamically preferred form of the reactants in the uncatalyzed model reaction in water is a solvent-separated ion pair (SSIP). Conversion of the SSIP into a contact ion pair, with a structure resembling that of the Michaelis complex (MC) for the reaction in the COMT active site, is unfavorable by 7 kcal mol(-1), largely due to reorganization of the solvent. We have considered alternative ways to estimate the so-called "cratic" free energy for bringing the reactant species together in the correct orientation for reaction but conclude that direct evaluation of the free energy of association by means of molecular dynamics simulation with a simple standard-state correction is probably the best approach. The latter correction allows for the fact that the size of the unit cell employed with the periodic boundary simulations does not correspond to the standard state concentration of 1 M. Consideration of MC-like species allows a helpful decomposition of the catalytic effect into preorganization and reorganization phases. In the preorganization phase, the substrates are brought together into the MC-like species, either in water or in the enzyme active site. In the reorganization phase, the roles of the enzymic and aqueous environments may be compared directly because reorganization of the substrate is about the same in both cases. Analysis of the electric field along the reaction coordinate demonstrates that in water the TS is destabilized with respect to the MC-like species because the polarity of the solute diminishes and consequently the reaction field is also decreased. In the enzyme, the electric field is mainly a permanent field and consequently there is only a small reorganization of the environment. Therefore, destabilization of the TS is lower than in solution, and the activation barrier is smaller.     

Toward the synthesis of reidispongiolide a: stereocontrolled synthesis of the C17-C22 and C23-C35 degradation fragments

[structure: see text] By relying on the asymmetric aldol reactions of chiral ketones, a highly stereocontrolled synthesis of each of the C(17)-C(22) and C(23)-C(35) degradation fragments of reidispongiolide A has been achieved. This permits a configurational assignment of the complete C(17)-C(36) region of this antimitotic macrolide, along with providing advanced intermediates for a projected total synthesis.     

A hard sphere model for order-disorder transitions in colloidal dispersions

Use of a hard sphere model and the concept of an effective hard sphere diameter of a colloidal particle with its associated double layer is reported. This method allows rapid determination of the order-disorder transition in colloidal dispersions and yields reasonable estimates of the osmotic pressures compared with “exact” Monte Carlo calculations.     

Chemical Constituents from the Root of Antidesma Pentandrum var. Barbatum

Investigation of the root extract of Antidesma pentandrum var. barbatum led to the isolation of seven new compounds, antidesmol ( 1 ), antidesmanins E ( 2 ) and F ( 3 ), antidesnone ( 4 ), antidesnol ( 5 ), barbatumols A ( 6 ) and B ( 7 ), together with 14 known compounds including sodium aristolochate‐I ( 10 ) and aristolochic acid‐I methyl ester ( 11 ).     

The structure and variable temperature 13c nmr spectra ofμ,μ′-(1,3-dithiolatocyclohepta-4,6-diene)hexacarbonyl-diiron(I)

μ,μ′-(1,3-Dithiolatocyclohepta-4,6-diene)hexacarbonyldiiron(I) was prepared by the reaction of 2,3,4-trithiabicyclo[4,3,1]deca-6,8-diene with Fe₂(CO)₉. The carbonyls undergo rapid site exchange within each Fe(CO)₃ group but there is no exchange of carbonyls between the two different Fe(CO)₃ moieties. The novel bicyclic nature of the bridging ligand results in a short iron—iron bond distance and a long sulfur—sulfur distance as compared to other members of this class.     

Mixed thin films of a cationic amphiphilic porphyrin and n-alkanes

Langmuir and Langmuir-Blodgett (LB) films of a cationic amphiphilic porphyrin mixed with n-alkanes octadecane and hexatriacontane were prepared and characterized, to examine the influence of the alkanes on film structure and stability. While the structure present in these films was controlled primarily by the porphyrin, the addition of the alkanes resulted in significant changes to both the phase behavior of the Langmuir films and the molecular arrangement of the LB films. These changes, as well as the observed chain length effects, are explained in terms of the intermolecular interactions present in the films.     

Alkaline hydrolysis of 2-(trifluoromethyl)imidazo[4,5-f] and -[4,5-h]quinolines

2-(Trifluoromethyl)imidazo[4,5-$\text{f}$] and -[4,5-$\text{h}$]quinoline have been prepared from 5(6),acetamido-2-(trifluoromethyl)benzimidazole and 7,8-diaminoquinoline respectively. These (trifluoromethyl)- quinolines like 2-(trifluoromethyl)imidazoles but unlike 2-(trifluoromethyl) benzimidazoles, undergo hydrolysis in dilute sodium hydroxide to give ultimately the corresponding imidazo[4,5-$\text{f}$] and -[4,5-$\text{h}$]- quinoline, respectively.     

Reactions of 29 Transition Metal Cations, in the Same Oxidation State and under the Same Gas-Phase Conditions, with Sulfur

A total of 29 transition metals (all except Tc), all as ions M(+), have been reacted with gaseous S(8). The reactivities and reaction products provide a unique set of comparative data on a fundamental reaction of the elements. The results underlie the interpretation of many other processes and compounds in condensed phases. Series of product ions [MS(y)()](+) are formed, with y generally starting at 4, and increasing with time through 8 up to 10, 12, 16, or 21 (for La(+)). A general mechanism is proposed, in which the first {MS(8)}(+) encounter complex is reactive and undergoes S-S bond scission and rearrangement around the metal, such that [MS(8)](+) is not an early product. The early transition metals react faster than later members of the series, and third row metals react about twice as fast as first row metals. The metals which are more chalcophilic in condensed-phase chemistry are apparently less so as M(+); Hg(+) does not form observable [HgS(y)()](+) (except for a very low yield of [HgS(3)](+)) and is remarkably less reactive with sulfur than most of the other metal ions. Simple electron transfer between M(+) and S(8) does not occur except possibly for Ir(+), but S(8)(+) is sometimes observed and is believed to be formed by electron transfer from S(8) to some [MS(y)()](+) complexes. Interpretation of the rates of reaction of the ions of groups 3, 4, and 5 with S(8) is complicated because they react with adventitious water in the cell forming oxo-species. The results are discussed in the context of condensed-phase metal polysulfide chemistry.     

A [2 + 2] cycloaddition route to dimethylaminomethylene vinamidinium salts

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).