Molecular Dynamics Simulation Study of the Negative Correlation in Antibody AZ28-Catalyzed Oxy-Cope Rearrangement

Asada, Toshio; Gouda, Hiroaki; Kollman, Peter A.

doi:10.1021/ja020774a

Cited by 12 publications

(18 citation statements)

References 33 publications

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“…This explains cases where there is no correlation between the high affinity of the hapten and the rate enhancement of the corresponding CA. [8,49] The difficulty in knowing a priori how effective a given TSA will be is probably the reason why a large part of the search for CAs now involves screenings rather than the original TSA concept. [50,51] Nevertheless, the search for improved TSAs can be helped by the present approaches.…”

Section: Discussionmentioning

confidence: 99%

On the Generation of Catalytic Antibodies by Transition State Analogues

Barbany¹,

Gutiérrez‐de‐Terán²,

Sanz³

et al. 2003

ChemBioChem

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The effective design of catalytic antibodies represents a major conceptual and practical challenge. It is implicitly assumed that a proper transition state analogue (TSA) can elicit a catalytic antibody (CA) that will catalyze the given reaction in a similar way to an enzyme that would evolve (or was evolved) to catalyze this reaction. However, in most cases it was found that the TSA used produced CAs with relatively low rate enhancement as compared to the corresponding enzymes, when these exist. The present work explores the origin of this problem, by developing two approaches that examine the similarity of the TSA and the corresponding transition state (TS). These analyses are used to assess the proficiency of the CA generated by the given TSA. Both approaches focus on electrostatic effects that have been found to play a major role in enzymatic reactions. The first method uses molecular interaction potentials to look for the similarity between the TSA and the TS and, in principle, to help in designing new haptens by using 3D quantitative structure-activity relationships. The second and more quantitative approach generates a grid of Langevin dipoles, which are polarized by the TSA, and then uses the grid to bind the TS. Comparison of the resulting binding energy with the binding energy of the TS to the grid that was polarized by the TS provides an estimate of the proficiency of the given CA. Our methods are used in examining the origin of the difference between the catalytic power of the 1F7 CA and chorismate mutase. It is demonstrated that the relatively small changes in charge and structure between the TS and TSA are sufficient to account for the difference in proficiency between the CA and the enzyme. Apparently the environment that was preorganized to stabilize the TSA charge distribution does not provide a sufficient stabilization to the TS. The general implications of our findings and the difficulties in designing a perfect TSA are discussed. Finally, the possible use of our approach in screening for an optimal TSA is pointed out.

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Section: Discussionmentioning

confidence: 99%

On the Generation of Catalytic Antibodies by Transition State Analogues

Barbany¹,

Gutiérrez‐de‐Terán²,

Sanz³

et al. 2003

ChemBioChem

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“…Although numerous improved functionals and basis sets for DFT calculations have been reported, it is difficult to justify the general reliabilities for these models or functionals. Thus, we used conventional B3LYP functionals − for all structural optimizations as well as the lanl2dz and 6-31G(d) basis sets for Pd and other atoms, respectively, considering the size of the molecules and the limitations of our computational resources. As the experimental measurements were carried out in MeCN, the polarizable continuum model (PCM) was applied to evaluate free energies during the structural optimizations using a dielectric constant of 36.64 for MeCN. , The energies of the optimized structures were refined using the larger 6-311++G(d,p) basis sets for C, H, and N in single-point energy calculations.…”

Section: Calculation Methodsmentioning

confidence: 99%

Theoretical Examination of the Plausible Reaction Process for Stereoselective Synthesis of Hexapole Helicene via a Palladium-Catalyzed [2 + 2 + 2] Cyclotrimerization of [5]Helicenyl Aryne

2020

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The reaction mechanisms of the plausible reaction process for the synthesis of hexapole helicene via a palladium-catalyzed [2 + 2 + 2] cyclotrimerization of [5]helicenyl aryne were examined using a theoretical approach. In a previous experimental study, this reaction selectively produced C 2symmetrical hexapole helicene, even though the D 3 -symmetrical structure is thermodynamically more stable. To clarify the mechanism underlying this reaction, density functional theory (DFT) and transition-state-theory calculations were used to evaluate the reaction profile and kinetic rate constants of the primary reactions. The thus obtained results suggest that the first step of the [2 + 2 + 2] cyclotrimerization is not a Diels−Alder reaction but an insertion of the helicenyl aryne into a metallacyclopentadiene. Subsequently, we clarified that the formation of the D 3 -symmetrical product is precluded by the high free-energy barrier of this reaction, while the C 2 -symmetrical product can be obtained at 300 K. Simulations of the time evolution of the molar fractions of the isomers were carried out based on the evaluated kinetic rate constants. The experimental result that the C 2 -symmetrical product is formed predominantly at 300 K was successfully reproduced in the simulations, while the isomerization into the more stable D 3 hexapole helicene structure is predicted to occur at 400 K.

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“…23 This value of the dielectric constant for the solute is consistent with our use of a nonpolarizable molecular mechanics force field; in this model, the solute response to charge fluctuations is estimated through explicit averaging of the conformations, rather than by use of an interior dielectric constant greater than unity. 24 The solvent dielectric constant of 80 is widely used for roomtemperature water. The contribution of the nonpolar term G np was calculated from where γ ) 0.00542 kcal/[mol Å 2 ], b ) 0.92 kcal/mol using the surface area estimation of the program MSMS.…”

Section: Model Structurementioning

confidence: 99%

Molecular Dynamics Simulation Study on Stabilities and Reactivities of NADH Cytochrome B5 Reductase

et al. 2008

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Binding free energies between coenzyme (FAD and NADH) and the apoenzyme of NADH-cytochrome b5 reductase (b5R) were estimated by applying the continuum Poisson-Boltzmann (PB) model to structures sampled from molecular dynamics simulations in explicit water molecules. Important residues for the enzymatic catalysis were clarified using a computational alanine scanning method. The binding free energies calculated by applying an alanine scanning method can successfully reproduce the trends of the measured steady-state enzymatic activities kcatNADH/KmNADH. Significant decreases in the binding free energy are expected when one of the four residues Arg91, Lys110, Ser127, and Thr181 is mutated into Ala. According to the results of the molecular dynamics simulation, Thr181 is considered to be one of the key residues that helps NADH to approach the isoalloxazine in FAD. Finally, we have constructed very simplified model systems and carried out density functional theory calculations using B3LYP/LANL2DZ//ROHF(or RHF)/LANL2DZ level of theory in order to elucidate a realistic and feasible mechanism of the hydride-ion transfer from NADH to FAD affected by HEME(Fe3+) as an electron acceptor. Our calculated results suggest that the electron and/or hydride-ion transfer reaction from NADH to FAD can be accelerated in the presence of HEME(Fe3+).

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Molecular Dynamics Simulation Study of the Negative Correlation in Antibody AZ28-Catalyzed Oxy-Cope Rearrangement

Cited by 12 publications

References 33 publications

On the Generation of Catalytic Antibodies by Transition State Analogues

On the Generation of Catalytic Antibodies by Transition State Analogues

Theoretical Examination of the Plausible Reaction Process for Stereoselective Synthesis of Hexapole Helicene via a Palladium-Catalyzed [2 + 2 + 2] Cyclotrimerization of [5]Helicenyl Aryne

Molecular Dynamics Simulation Study on Stabilities and Reactivities of NADH Cytochrome B5 Reductase

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