Piotr Paneth

ISOEFF98. A program for studies of isotope effects using Hessian modifications

A new program for calculations of isotope effects has been developed. It requires only force constants for substrate and transition state as the external data. All other calculational steps are integrated into the program. ISOEFF98 has features of Hessian modification and scale factor optimization. The first of these allows studies of isotope effect changes upon weakening or strengthening of internal coordinates. The second feature allows fitting of the calculated isotope effect to the experimental value by scaling of molecular frequencies.

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B12-dependent mutase

Hydrogen transfer reactions catalyzed by coenzyme B12-dependent methylmalonyl-CoA mutase have very large kinetic isotope effects, indicating that they proceed by a highly quantal tunneling mechanism. We explain the kinetic isotope effect by using a combined quantum mechanical/molecular mechanical potential and semiclassical quantum dynamics calculations. Multidimensional tunneling increases the magnitude of the calculated intrinsic hydrogen kinetic isotope effect by a factor of 3.6 from 14 to 51, in excellent agreement with experimental results. These calculations confirm that tunneling contributions can be large enough to explain even a kinetic isotope effect >50, not because the barrier is unusually thin but because corner-cutting tunneling decreases the distance over which the system tunnels without a comparable increase in either the effective potential barrier or the effective mass for tunneling.

Binding Isotope Effects

1. Isotope Effects A 1.1. Equilibrium Isotope Effects B 1.2. Kinetic Isotope Effects B 1.3. Notes on Nomenclature C 1.4. Notes on Measuring of Isotope Effects C 2. Applications of Binding Isotope Effects D 2.1. Ligand-Binding Enzymes E 2.1.1. α-(2→6)-Sialyltransferase E 2.1.2. trans-Salidase F 2.1.3. Thymidine Phosphorylase F 2.1.4. Purine Nucleoside Phosphorylase I 2.1.5. Sarcosine Dehydrogenase J 2.1.6. Chorismate Mutase K 2.1.7. Cortcosteroid-Binding Globulin N 2.1.8. Hexokinase O 2.1.9. Alcohol Dehydrogenase P 2.1.10. Lactate Dehydrogenase P 2.2. Ligand-Carrying Proteins Q 2.2.1. Hemoglobin and Myoglobin Q 2.2.2. Cytochrome P450cam Q 2.2.3. Hemerythrin R 2.2.4. Hemocyanin R 2.2.5. Taurine Dioxygenase, (S)-(2)-Hydroxypropylphosphonic Acid, Epoxidase, and 1-Aminocyclopropyl-1-carboxylic Acid Oxidase R 2.2.6. Human Serum Albumin R 2.3. Nonbiological Host−Guest Systems S 2.3.1. Calix[4]resorcarene Hosts S 2.3.2. Cyclodextrins S 2.3.3. Cylindrical Molecular Capsule Host S 2.3.4. Hemicarcerand S 2.3.5. Deep-Cavity Cavitand Host V 2.3.6. Self-Assembled Capsule 1·4BF4 X 2.3.7. Self-Assembled [Ga4L6] 12− Host X 3. Conclusions Y Author Information Z Corresponding Author Z Notes Z Biographies Z Acknowledgments Z References AA

Assessing Molecular Docking Tools for Relative Biological Activity Prediction: A Case Study of Triazole HIV-1 NNRTIs

Molecular docking is a technique widely used in drug design. Many studies exist regarding the general accuracy of various docking programs, but case studies for a given group of related compounds are rare. In order to facilitate identification of novel triazole HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), several docking and scoring programs were evaluated for their ability to predict relative biological activity of 111 known 1,2,4-triazole and 76 other azole type NNRTIs. Glide, FlexX, Molegro Virtual Docker, AutoDock Vina, and Hyde were used. Different protocols, settings, scoring functions, and interaction terms were analyzed. We have found that the programs performance was dependent on the data set, indicating the importance of choosing good quality target data for any comparative study. The results suggest that after optimization and proper validation, some of the molecular docking programs can help in predicting relative biological activity of azole NNRTIs.

DFT study of trichloroethene reaction with permanganate in aqueous solution.

The mechanism of the environmentally important reaction between permanganate anion and trichloroethene (TCE) has been studied theoretically using modern DFT functional. It has been shown that IEFPCM/M05-2X/aug-cc-pVDZ theory level yields activation parameters and carbon isotopic fractionation factor in excellent agreement with the experimental data. Obtained results indicate that this reaction proceeds via the 3+2 mechanism with a very early transition state, in which the new C-O bonds are formed only in about 20%. An alternative, stepwise mechanism that involves initial formation of a single new C-O bond and a C-Mn bond, followed by rearrangement to the permanganate-TCE adduct, has been found to be more energetically demanding and in disagreement with the experimental isotopic fractionation.

Isotopic analysis of oxidative pollutant degradation pathways exhibiting large H isotope fractionation.

Oxidation of aromatic rings and its alkyl substituents are often competing initial steps of organic pollutant transformation. The use of compound-specific isotope analysis (CSIA) to distinguish between these two pathways quantitatively, however, can be hampered by large H isotope fractionation that precludes calculation of apparent (2)H-kinetic isotope effects (KIE) as well as the process identification in multi-element isotope fractionation analysis. Here, we investigated the C and H isotope fractionation associated with the transformation of toluene, nitrobenzene, and four substituted nitrotoluenes by permanganate, MnO4(-), to propose a refined evaluation procedure for the quantitative distinction of CH3-group oxidation and dioxygenation. On the basis of batch experiments, an isotopomer-specific kinetic model, and density functional theory (DFT) calculations, we successfully derived the large apparent (2)H-KIE of 4.033 ± 0.20 for the CH3-group oxidation of toluene from H isotope fractionation exceeding >1300‰ as well as the corresponding (13)C-KIE (1.0324 ± 0.0011). Experiment and theory also agreed well for the dioxygenation of nitrobenzene, which was associated with (2)H- and (13)C-KIEs of 0.9410 ± 0.0030 (0.9228 obtained by DFT) and 1.0289 ± 0.0003 (1.025). Consistent branching ratios for the competing CH3-group oxidation and dioxygenation of nitrotoluenes by MnO4(-) were obtained from the combined modeling of concentration as well as C and H isotope signature trends. Our approach offers improved estimates for the identification of contaminant microbial and abiotic oxidation pathways by CSIA.

Modeling of isotope effects on binding oxamate to lactic dehydrogenase

A new crystal structure of the rabbit muscle L-lactic dehydrogenase (PDB code 3H3F) has been determined. The independent unit of this structure contains two tetramers, each of them with a unique constitution of two active sites with the open loop conformation and two with the loops closed over the actives sites. On the basis of this structure, interactions of an inhibitor, oxamate anion, with the protein have been modeled using different hybrid schemes that involved B3LYP/6-31++G(d,p) DFT theory level in the QM layer. In ONIOM calculations, either Amber (QM:MM) or one of the three semiempirical parametrizations, AM1, PM3, and RM1 (QM:QM) was used, while in the traditional QM/MM scheme, the OPLS-AA force field was used for the outer layer. Normal modes of vibrations of oxamate in aqueous solution and in the active site of the enzyme were used to calculate binding isotope effects. On the basis of the comparison of the values obtained theoretically with those experimentally determined for the oxygen atoms of the carboxylic group of oxamate it was concluded that the DFT/OPLS-AA scheme, applied to the dimer consisting of two chains, one with the open loop and the other with the closed loop conformation, provides the best description of the active site. Calculations of the binding isotope effects of the other atoms of oxamate suggest that nitrogen isotope effect may be useful for the experimental differentiation between open and closed loop conformations.

Extending limits of chlorine kinetic isotope effects.

Chlorine kinetic isotope effects exceeding semiclassical limits were observed in enzyme-catalyzed reactions, but their source has not been yet identified. Herein we show that unusually large chlorine kinetic isotope effects are associated with reactions in which chlorine is the central atom that is being passed between two heavy atoms. The origin of these large values is the ratio of imaginary frequencies for light-to-heavy species (the so-called temperature-independent factor).

A DFT Study of the Kinetic Isotope Effects on the Competing SN2 and E2 Reactions between Hypochlorite Anion and Ethyl Chloride.

Kinetic isotope effects (KIEs) on the two alternative reactions, SN2 and E2, between hypochlorite anion and ethyl chloride in water have been studied theoretically using B3LYP and M06-2X functionals. It has been found that the latter one yields more correct geometries and energetics. Although, in the qualitative sense, KIEs obtained using both DFT functionals are in agreement, interpretation of some of them, like (18)O-KIE in the present case, leads to different mechanistic conclusions.

Theoretical evaluation of the hydrogen kinetic isotope effect on the first step of the methylmalonyl-CoA mutase reaction.

We have calculated hydrogen kinetic isotope effects (KIEs) for the first step of the methylmalonyl-CoA mutase reaction, including multidimensional tunneling correction at the zero curvature (ZCT) level, and compared them with the experimental values. Both alternative mechanisms of this step, concerted and stepwise, can be accommodated. It turned out to be essential to include Arg207 hydrogen-bonded to the reactant in the mechanism predicting simultaneous breaking of the Co-C bond of AdoCbl and hydrogen atom transfer. The consequence of the stepwise mechanism is a much larger facilitation of the homolytic dissociation of the carbon-cobalt bond by the enzyme than currently appreciated; our results suggest lowering of the activation energy by about 23 kcal mol(-1). We have also shown that large hydrogen KIEs of tunneling origin do not necessarily break the Swain-Schaad equation. Furthermore, when this equation does not hold, the exponent may be smaller in the presence of tunneling than it is at the semi-classical limit, indicating that nonclassical behavior may be a more common phenomenon than expected.