Gibbs energies of activation for reacting systems with multiple reactant-state and transition-state conformations.

Three distinct procedures for obtaining the effective Gibbs energies of activation from computed energies for a reaction involving multiple reactant-state (RS) and transition-state (TS) conformers are shown to be equivalent. If Boltzmann-weighted average Gibbs energies for RS and TS are evaluated, then the Gibbs energy contribution from entropy of mixing of both RS and TS conformers must also be included in order to obtain the correct value for the effective Gibbs energy of activation. Application to a solvolytic reaction of 4,4’-dimethoxybenzhydrylpyridinium cation, which is shown to satisfy the Curtin-Hammett principle with rapid interconversion of RS conformers, demonstrates the use of each procedure for evaluation of the effective Gibbs energy of activation

Influence of Dielectric Environment upon Isotope Effects onGlycoside Heterolysis: Computational Evaluation and AtomicHessian Analysis

Isotope effects depend upon the polarity of the bulk medium in which a chemical process occurs. Implicit solvent calculations with molecule-shaped cavities show that the equilibrium isotope effect (EIE) for heterolysis of the glycosidic bonds in 5′-methylthioadenosine and in 2-(p-nitrophenoxy)tetrahydropyran, both in water, are very sensitive in the range 2 ≤ ε ≤ 10 to the relative permittivity of the continuum surrounding the oxacarbenium ion. However, different implementations of nominally the same PCM method can lead to opposite trends being predicted for the same molecule. Computational modeling of the influence of the inhomogeneous effective dielectric surrounding a substrate within the protein environment of an enzymic reaction requires an explicit treatment. The EIE (KH/KD) for transfer of cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl cations from water to cyclohexane is predicted by B3LYP/6-31+G(d) calculations with implicit solvation and confirmed by B3LYP/6-31+G(d)/OPLS-AA calculations with averaging over many explicit solvation configurations. Atomic Hessian analysis, whereby the full Hessian is reduced to the elements belonging to a single atom at the site of isotopic substitution, reveals a remarkable result for both implicit and explicit solvation: the influence of the solvent environment on these EIEs is essentially captured completely by only a 3 × 3 block of the Hessian, although these values must correctly reflect the influence of the whole environment. QM/MM simulation with ensemble averaging has an important role to play in assisting the meaningful interpretation of observed isotope effects for chemical reactions both in solution and catalyzed by enzymes

The Trans-Pacific Partnership: Negotiations and Issues for Congress

[Excerpt] The Trans-Pacific Partnership (TPP) is a potential free trade agreement (FTA) among 11, and perhaps more, countries. The United States and 10 other countries of the Asia-Pacific region— Australia, Brunei, Canada, Chile, Malaysia, Mexico, New Zealand, Peru, Singapore, and Vietnam—are negotiating the text of the FTA. Canada and Mexico participated for the first time in the Auckland round of negotiations in December 2012, and Japan recently announced it would seek to participate in the negotiations. With 29 chapters under negotiation, the TPP partners envision the agreement to be “comprehensive and high-standard,” in that they seek to eliminate tariffs and non-tariff barriers to trade in goods, services, and agriculture, and to establish rules on a wide range of issues including foreign direct investment and other economic activities. They also strive to create a “21st-century agreement” that addresses new and cross-cutting issues presented by an increasingly globalized economy. The TPP draws congressional interest on a number of fronts. Congress would have to approve implementing legislation for U.S. commitments under the agreement to enter into force. In addition, under long-established executive-legislative practice, the Administration notifies and consults with congressional leaders, before, during, and after trade agreements have been negotiated. Furthermore, the TPP will likely affect a range of sectors and regions of the U.S. economy of direct interest to Members of Congress and could influence the shape and path of U.S. trade policy for the foreseeable future. This report examines the issues related to the proposed TPP, the state and substance of the negotiations (to the degree that the information is publically available), the specific areas under negotiation, the policy and economic contexts in which the TPP would fit, and the issues for Congress that the TPP presents. The report will be revised and updated as events warrant

Computational exploration of α-lactone rearrangements and the cyclic halonium zwitterion from bromination of acrylate anion in water: implicit vs. explicit solvation

In memory of Jonathan Williams, a valued colleague of incisive intellect (and regarded by undergraduates as ‘the better-looking Prof. Williams’ in the Department). Bromomethyloxiranone has a much larger repertoire of molecular acrobatics than previously recognised: conformational isomerism, degenerate rearrangement that exchanges O atoms in the α-lactone ring, and epimerisation, all of which occur with lower barriers than dyotropic rearrangement to the more stable β-lactone. DFT calculations (B3LYP/6-31 + G∗) with implicit solvation (PCM) by water predict the cyclic bromonium zwitterion (formally derived from addition of Br + to acrylate anion) to be a transition structure but QM/MM simulations, combining the same DFT method with explicit solvation by many MM water molecules and using molecular dynamics to obtain free-energy profiles and surfaces, reconfirms the status of the cyclic bromonium as an intermediate. </p

Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational Modeling

The origin of enzyme catalysis remains a question of debate despite much intense study. We report a QM/MM theoretical study of the SN2 methyl transfer reaction catalyzed by a glycine N-methyltransferase (GNMT) and three mutants to test whether recent experimental observations of rate-constant reductions and variations in inverse secondary α-3H kinetic isotope effects (KIEs) should be attributed to changes in the methyl donor−acceptor distance (DAD): is catalysis due to a compression effect? Semiempirical (AM1) and DFT (M06-2X) methods were used to describe the QM subset of atoms, while OPLS-AA and TIP3P classical force fields were used for the protein and water molecules, respectively. The computed activation free energies and KIEs are in good agreement with experimental data, but the mutations do not meaningfully affect the DAD: compression cannot explain the experimental variations on KIEs. On the contrary, electrostatic properties in the active site correlate with the catalytic activity of wild type and mutants. The plasticity of the enzyme moderates the effects of the mutations, explaining the rather small degree of variation in KIEs and reactivities

Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis.

DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN*ANint‡ mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with Cα–Onu ≈ 2 ± 0.4 Å and Cα–Olg ≈ 3 ± 0.5 Å. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge

Theoretical site-directed mutagenesis. The Asp168Ala mutant of L-Lactate Dehydrogenase

The reduction of pyruvate to lactate catalyzed by the L-Lactate dehydrogenase has been studied in this paper by means of hybrid Quantum Mechanical / Molecular Mechanical simulations. A very flexible molecular model consisting on the full tetramer of the enzyme, together with the cofactor NADH, the substrate and solvent water molecules has allowed to theoretically mimic site directed mutagenesis studies, most of them previously experimentally performed. The potential energy surfaces obtained for every single mutation, compared with the one corresponding to the native enzyme, have been used to trace the possible reaction pathways and to locate and characterize the structures corresponding to the stationary points. The analysis of the results has been a very powerful tool to conclude about the role of key residues on the vacuole formed in the active site of the enzyme. Our results are in very good agreement with the previous conclusions derived from site directed mutagenesis. This strategy can be extrapolated to other enzyme systems thus opening the door of a very promising methodology that, in combination with the appropriate experimental technique, will enable us to describe enzyme catalysis phenomenon and the particular role of the residues that form the protein. This knowledge placed us in a privileged position to modify the activity of enzymes and to propose efficient inhibitor