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Free energy perturbations advantages

The differences in the rate constant for the water reaction and the catalyzed reactions reside in the mole fraction of substrate present as near attack conformers (NACs).171 These results and knowledge of the importance of transition-state stabilization in other cases support a proposal that enzymes utilize both NAC and transition-state stabilization in the mix required for the most efficient catalysis. Using a combined QM/MM Monte Carlo/free-energy perturbation (MC/FEP) method, 82%, 57%, and 1% of chorismate conformers were found to be NAC structures (NACs) in water, methanol, and the gas phase, respectively.172 The fact that the reaction occurred faster in water than in methanol was attributed to greater stabilization of the TS in water by specific interactions with first-shell solvent molecules. The Claisen rearrangements of chorismate in water and at the active site of E. coli chorismate mutase have been compared.173 It follows that the efficiency of formation of NAC (7.8 kcal/mol) at the active site provides approximately 90% of the kinetic advantage of the enzymatic reaction as compared with the water reaction. [Pg.415]

Thus, one may fairly compare the free-energy perturbation technique with the molecular mechanics methods in order to have a correct assessment of the various advantages associated with the estimation of the relative binding affinities of COX-2, inhibitors. [Pg.95]

This chapter reviews some theoretical aspects of the two most popular free energy difference methods, thermodynamic perturbation and thermodynamic integration, as well as assumptions and approximations made in the implementation. Advantages and disadvantages of certain implementations are discussed, and general recommendations are given for the practical application of these methods. [Pg.82]


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Free energy perturbation

Perturbation energy

Perturbed energy

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