Transition-state modeling with empirical force fields

Eksterowicz, John; Houk, K. N.

doi:10.1021/cr00023a006

Cited by 166 publications

(110 citation statements)

References 43 publications

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“…We are interested only in the simulated structures, because the total energies calculated in this way are meaningless. Transition-state modeling with empirical force fields was previously performed to study various organic reactions, and the theoretical justification of the transition-state modeling was discussed in detail by Eksterowicz and Houk (29).…”

Section: Methodsmentioning

confidence: 99%

Computational redesign of human butyrylcholinesterase for anticocaine medication

Pan

Gao

Yang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

174

312

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Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (؊)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (؊)-cocaine hydrolysis catalyzed by A199S͞S287G͞A328W͞Y332G BChE should be significantly stronger than that in the TS1 structure for (؊)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S͞ S287G͞A328W͞Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (؊)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an Ϸ(456 ؎ 41)-fold improved catalytic efficiency of A199S͞S287G͞A328W͞Y332G BChE against (؊)-cocaine. This is a unique study to design an enzyme mutant based on transitionstate simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery. molecular dynamics ͉ rational design ͉ transition-state stabilization ͉ cocaine ͉ enzyme-substrate binding C ocaine is recognized as the most reinforcing of all drugs of abuse (1-3). The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority (4-6). However, cocaine mediates its reinforcing and toxic effects by blocking neurotransmitter reuptake, and the classical pharmacodynamic approach has failed to yield small-molecule receptor antagonists because of the difficulties inherent in blocking a blocker (1-5). An alternative to receptor-based approaches is to interfere with the delivery of cocaine to its receptors or accelerate its metabolism in the body (5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). An ideal molecule for this purpose should be a potent enzyme catalyzing the hydrolysis of cocaine into biologically inactive metabolites. The dominant pathway for cocaine metabolism in primates is butyrylcholinesterase (BChE)-catalyzed hydrolysis at the benzoyl ester group (Fig. 3, which is published as supporting information on the PNAS web site), and the metabolites are all biologically inactive (5, 18). Clearly, BChE-catalyzed hydrolysis of cocaine at the benzoyl ester is the metabolic pathway most suitable for amplification. However, the catalytic activity of this plasma enzyme is Ϸ1,000-fold lower against the naturally occurring (Ϫ)-cocaine than that against the biologically inactive (ϩ)-cocaine enantiomer (19)(20)(21)(22). (ϩ)-cocaine can be cleared from plasma in seconds, before partitioning into the CNS, whereas (Ϫ)-cocaine has a plasma half-life of Ϸ45-90 min, long enough for ...

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Section: Methodsmentioning

confidence: 99%

Computational redesign of human butyrylcholinesterase for anticocaine medication

Pan

Gao

Yang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

174

312

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“…Technically, we can maintain the bond lengths of the forming and breaking covalent bonds by simply fixing all atoms within the reaction center, by using some constraints on the forming and breaking covalent bonds, or by redefining the forming and breaking covalent bonds. 31 The forming and breaking covalent bonds in the transition state will be called "transition" bonds below, for convenience. It should be pointed out that the only purpose of performing such type of MD or FEP simulation on a transition state is to examine the dynamic change of the protein environment surrounding the reaction center and the interaction between the reaction center and the protein environment.…”

Section: General Consideration Of the Transition-state Simulationmentioning

confidence: 99%

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

et al. 2007

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A novel computational protocol based on free energy perturbation (FEP) simulations on both the free enzyme and transition state structures has been developed and tested to predict the mutation-caused shift of the free energy change from the free enzyme to the rate-determining transition state for human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (-)-cocaine. The calculated shift, denoted by ΔΔG(1→2), of such kind of free energy change determines the catalytic efficiency (k cat /K M ) change caused by the simulated mutation transforming enzyme 1 to enzyme 2. By using the FEP-based computational protocol, the ΔΔG(1→2) values for the mutations A328W/Y332A → A328W/Y332G and A328W/Y332G → A328W/Y332G/A199S were calculated to be -0.22 and -1.94 kcal/mol, respectively. The calculated ΔΔG(1→2) values predict that the change from the A328W/Y332A mutant to the A328W/Y332G mutant should slightly improve the catalytic efficiency and that the change from the A328W/Y332G mutant to the A328W/Y332G/A199S mutant should significantly improve the catalytic efficiency of the enzyme for the (-)-cocaine hydrolysis. The predicted catalytic efficiency increases are supported by the experimental data showing that k cat /K M = 8.5 × 10 6 , 1.4 × 10 7 , and 7.2 × 10 7 min -1 M -1 for the A328W/Y332A, A328W/Y332G, and A328W/Y332G/A199S mutants, respectively. The qualitative agreement between the computational and experimental data suggests that the FEP simulations may provide a promising protocol for rational design of highactivity mutants of an enzyme. The general computational strategy of the FEP simulation on a transition state can be used to study the effects of a mutation on the activation free energy for any enzymatic reaction.

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“…Another major shortcoming of MM is its extension to the computation of transition states; this is by no means trivial. 6 One possible method to overcome the shortcomings of both approaches is to mix quantum mechanics and MM descriptions in different parts of the same molecule. In this way, the difficult parts of the molecule (those containing nonparameterized atoms, uncommon interactions, or atoms directly participating in the transition state of a reaction) can be computed with the expensive quantum mechanical methodology, while easy parts of the molecule, containing well-parameterized atoms and simple interactions, can be computed in a cheaper way with molecular mechanics.…”

Section: Introductionmentioning

confidence: 99%

IMOMM: A new integrated ab initio + molecular mechanics geometry optimization scheme of equilibrium structures and transition states

1995

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A new computational scheme integrating ab initio and molecular mechanics descriptions in different parts of the same molecule is presented. In contrast with previous approaches, this method is especially designed to allow the introduction of molecular mechanics corrections in full geometry optimizations concerning problems usually studied through ab initio calculations on model systems. The scheme proposed in this article intends to solve some of the systematic error associated with modeling through the use of molecular mechanics corrections. This method, which does not require any new parameter, evaluates explicitly the energy derivatives with respect to geometrical parameters and therefore has a straightforward application to geometry optimization. Examples of its performance on two simple cases are provided: the equilibrium geometry of cyclopropene and the energy barriers on S , 2 reactions of alkyl chloride systems. Results are in satisfactory agreement with those of full ab initio calculations in both cases. 0 1995 by John Wiley & Sons, Inc.

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Transition-state modeling with empirical force fields

Cited by 166 publications

References 43 publications

Computational redesign of human butyrylcholinesterase for anticocaine medication

Computational redesign of human butyrylcholinesterase for anticocaine medication

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

IMOMM: A new integrated ab initio + molecular mechanics geometry optimization scheme of equilibrium structures and transition states

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