Biomedical subjects

Donald G Truhlar

Publications and source records attributed to Donald G Truhlar.

8 recordsLinked to original sources

PubMed2003

Importance of substrate and cofactor polarization in the active site of dihydrofolate reductase.

By using a combined quantum-mechanical and molecular-mechanical potential in molecular dynamics simulations, we have investigated the effects of the enzyme electric field of dihydrofolate reductase on the electronic polarization of its 5-protonated dihydrofolate substrate at various stages of the catalyzed hydride transfer reaction. Energy decomposition of the total electrostatic interaction energy between the ligands and the enzyme shows that the polarization effect is 4% of the total electrostatic interaction energy, and, significantly, it accounts for 9kcal/mol of transition state stabilization relative to the reactant state. Therefore it is essential to take account of substrate polarization for quantitative interpretation of enzymatic function and for calculation of binding free energies of inhibitors to a protein. Atomic polarizations are calculated as the differences in the average atomic charges on the atoms in gas phase and in molecular simulations of the enzyme; this analysis shows that the glutamate tail and the pterin ring are the highly polarized regions of the substrate. Electron density difference plots of the reactant and product complexes at instantaneous configurations in the enzyme active center confirm the inferences made on the basis of partial atomic charges.

Binding Sites↗

PubMed2003

Carbon tunneling from a single quantum state.

We observed ring expansion of 1-methylcyclobutylfluorocarbene at 8 kelvin, a reaction that involves carbon tunneling. The measured rate constants were 4.0 x 10(-6) per second in nitrogen and 4 x 10(-5) per second in argon. Calculations indicated that at this temperature the reaction proceeds from a single quantum state of the reactant so that the computed rate constant has achieved a temperature-independent limit. According to calculations, the tunneling contribution to the rate is 152 orders of magnitude greater than the contribution from passage over the barrier. We discuss environmental effects of the solid-state inert-gas matrix on the reaction rate.

Journal Article↗

PubMed2003

Hydride transfer catalyzed by xylose isomerase: mechanism and quantum effects.

We have applied molecular dynamics umbrella-sampling simulation and ensemble-averaged variational transition state theory with multidimensional tunneling (EA-VTST/MT) to calculate the reaction rate of xylose-to- xylulose isomerization catalyzed by xylose isomerase in the presence of two Mg2+ ions. The calculations include determination of the free energy of activation profile and ensemble averaging in the transmission coefficient. The potential energy function is approximated by a combined QM/MM/SVB method involving PM3 for the quantum mechanical (QM) subsystem, CHARMM22 and TIP3P for the molecular mechanical (MM) environment, and a simple valence bond (SVB) local function of two bond distances for the hydride transfer reaction. The simulation confirms the essential features of a mechanism postulated on the basis of kinetics and X-ray data by Whitlow et al. (Whitlow, M.; Howard, A. J.; Finzel, B. C.; Poulos, T. L.; Winborne, E.; Gilliland, G. L. Proteins 1991, 9, 153) and Ringe, Petsko, and coworkers (Labie, A.; Allen, K.-N.; Petsko, G. A.; Ringe, D. Biochemistry 1994, 33, 5469). This mechanism involves a rate-determining 1,2-hydride shift with prior and post proton transfers. Inclusion of quantum mechanical vibrational energy is important for computing the free energy of activation, and quantum mechanical tunneling effects are essential for computing kinetic isotope effects (KIEs). It is found that 85% of the reaction proceeds by tunneling and 15% by overbarrier events. The computed KIE for the ratio of hydride to deuteride transfer is in good agreement with the experimental results. The molecular dynamics simulations reveal that proton and hydride transfer reactions are assisted by breathing motions of the mobile Mg2+ ion in the active site, providing evidence for concerted motion of Mg2+ during the hydride transfer step.

Aldose-Ketose Isomerases↗

PubMed2003

Electrostatic component of solvation: comparison of SCRF continuum models.

We report a systematic comparison of the electrostatic contributions to the free energy of solvation from three different kinds of quantum mechanical self-consistent reaction field (SCRF) methods. We also compare the liquid-phase dipole moments as a measure of the solute's response to the reaction field of the solvent. In particular, we compare these quantities for the generalized Born model as implemented in the SM5.42R method, the multipolar expansion model developed at Nancy, and the MST version of the polarizable continuum model. All calculations are carried out at the HF/6-31G(d) level. The effects of various choices of solute cavities and representations of the charge density are examined. The test set consists of 18 molecules containing prototypical polar groups, and three different values of the dielectric permittivity are considered.

Journal Article↗

PubMed2002

Structures and aggregation states of fluoromethyllithium and chloromethyllithium carbenoids in the gas phase and in ethereal solvent.

Using high-level quantum mechanical calculations and various models to account for solvation effects, monomers and dimers of fluoromethyllithium and chloromethyllithium carbenoids are studied in the gas phase and in dimethyl ether solvent. A combination of explicit microsolvation and a continuum reaction field is required to account fully for the structural and energetic effects of solvation. One important effect of solvent is the stabilization of charge-separated structures in which the lithium-halogen distance is much greater than in the gas-phase structures. At the most complete level of theory the 173 K standard-state free energy of dimerization of fluoromethyllithium in dimethyl ether is predicted to be -0.9 kcal mol(-)(1), while that for chloromethyllithium in the same solvent is predicted to be 3.7 kcal mol(-)(1). This suggests that, under typical experimental conditions, dimers of chloroalkyllithiums will not be observed, while dimers of fluoroalkyllithiums may contribute to the equilibrium population at a detectable level.

Journal Article↗

PubMed2002

Quantum dynamics of hydride transfer catalyzed by bimetallic electrophilic catalysis: synchronous motion of Mg(2+) and H(-) in xylose isomerase.

Xylose isomerase exhibits a bridged-bimetallic active-site motif in which the substrate is bound to two metals connected by a glutamate bridge, and X-ray crystallographic studies suggest that metal movement is involved in the hydride transfer rate-controlling catalytic step. Here we report classical/quantal dynamical simulations of this step that provide new insight into the metal motion. The potential energy surface is calculated by treating xylose with semiempirical molecular orbital theory augmented by a simple valence bond potential and the rest of the system by molecular mechanics. The rate constant for the hydride-transfer step was calculated by ensemble-averaged dynamical simulations including both variational transition-state theory for determination of the statistically averaged dynamical bottleneck and optimized multidimensional tunneling calculations. The dynamics calculations include 25 317 atoms, with quantized vibrational free energy in 89 active-site degrees of freedom, and with 32 atoms moving through static secondary zone transition-state configurations in the quantum tunneling simulation. Our simulations show that the average Mg-Mg distance R increases monotonically as a function of the hydride-transfer progress variable z. The range of the average R along the reaction path is consistent with the X-ray structure, thus providing a dynamical demonstration of the postulated role of Mg in catalysis. We also predicted the primary deuterium kinetic isotope effect (KIE) for the chemical step. We calculated a KIE of 3.8 for xylose at 298 K, which is consistent with somewhat smaller experimentally observed KIEs for glucose substrate at higher temperatures. More than half of our KIE is due to tunneling; neglecting quantum effects on the reaction coordinate reduces the calculated KIE to 1.8.

Aldose-Ketose Isomerases↗

PubMed2002

The incorporation of quantum effects in enzyme kinetics modeling.

We present an overview of new procedures for including quantum mechanical effects in enzyme kinetics. Quantum effects are included in three ways: (1) The electronic structure of the atoms in the catalytic center is treated quantum mechanically in order to calculate a realistic potential energy surface for the bond rearrangement process. (2) The discrete nature of quantum mechanical vibrational energies is incorporated in the treatment of nuclear motion for computing the potential of mean force. (3) Multidimensional tunneling contributions are included. These procedures are illustrated by applications to proton abstractions catalyzed by enolase and methylamine dehydrogenase and hydride-transfer reactions by alcohol dehydrogenase and xylose isomerase.

Catalysis↗

PubMed2001

Quantum mechanical methods for enzyme kinetics.

This review discusses methods for the incorporation of quantum mechanical effects into enzyme kinetics simulations in which the enzyme is an explicit part of the model. We emphasize three aspects: (a) use of quantum mechanical electronic structure methods such as molecular orbital theory and density functional theory, usually in conjunction with molecular mechanics; (b) treating vibrational motions quantum mechanically, either in an instantaneous harmonic approximation, or by path integrals, or by a three-dimensional wave function coupled to classical nuclear motion; (c) incorporation of multidimensional tunneling approximations into reaction rate calculations.

Computer Simulation↗