Quantum mechanics hydrolysis

J. Pitarch, J. L. Pascual-Ahuir, E. Silla, I. Tunon, V. Moliner, Analysis of a Concerted Mechanism in /3-Lactam Enzymatic Hydrolysis. A Quantum Mechanics/Molecular Mechanics Study , J. Chem. Soc., Perkin Trans. 2, 1999, 1351-1356. 

B. Waszkowycz, I. H. Hiller, N. Gensmantel, D. W. Payling, A Combined Quantum Mechanical/Molecular Mechanical Model of the Potential Energy Surface of Ester Hydrolysis by the Enzyme Phospholipase A2 ,. /. Chem. Soc., Perkin Trans. 2 1991, 225-231. 

A new, more general, way to combine ab initio quantum mechanical calculations with classical mechanical free-energy perturbation approach (QM/FE approach) to calculate the energetics of enzyme-catalysed reactions and the same reaction in solution has been reported." The calculated free energies were in fairly good agreement with the experimental data for the activation energies of the first test case, amide hydrolysis in trypsin and in aqueous solution. 

A concerted rather than a stepwise reaction involving a tetrahedral intermediate is supported for die papain-catalysed hydrolysis of amides. The TS for die hydrolysis has been determined by using a hybrid quantum mechanical/molecular mechanical potential, QM(AM1)/MM.216... 

The change in total energy between the infinitely separated reactants and the species at the energy minimum of the reaction co-ordinate curve will not be comparable to the heat of reaction (because thermodynamics is neglected in the quantum mechanical model). Nevertheless, the energy change can be quite useful on a relative basis in the case of comparing the hydrolysis of a series of closely related compounds. 

Berger and Wolfe (1996) reported a correlation of hydrolysis data for 12 sulfonylurea herbicides. The use of bond strength or Hammett a constants was impossible because of the complex structures of the compounds. The hydrolysis pathways for this class of compounds are also more complex, but the use of quantum mechanical parameters provided the detailed structural information needed to develop a useful correlation. As a result of the many different functional groups, several reaction pathways are available depending on the substituents. Also, there is a complicating pH effect on the pathways and the kinetics of hydrolysis as shown by product studies. The 12 herbicides used in this study are listed in Table 13.4, and the pseudo first-order hydrolysis rate constants are given in Table 13.5. Figure 13.2 shows the basic structure of these compounds. 

A 1,10-phenanthroline-containing polyamine macrocycle (78) was designed to complex with Zn2+ ion and, because of the rigidity of the phenanthroline moiety, leave some free binding sites at the metal for ligands such as water, which easily depro-tonate to give stable hydroxo species. The hydrolysis of methyl acetate in the gas phase by such a monohydroxy-Zn(II) complex [Zn(78)(OH)]+ has been investigated by quantum mechanical procedures and some pathways delineated.78... 

Lasaga, A. C., and G. V. Gibbs (1990). Ab initio quantum mechanical calculations on water-rock interactions absorption and hydrolysis reactions. Am. J. Sci. 290, 263-95. 

A quantum mechanical method has been used to study the TSs of the uridine phosphorylation reaction and an acid-catalysed Sn2 is the main mode of reaction. The ribonucleotide sulfur analogue 2 -deoxy-2 -thiouridine 3 -(p-nitrophenyl phosphate) (295) undergoes transphosphorylation to give 2, 3 -cychc phosphorothioate (296) followed by hydrolysis to give 2 -deoxy-2 -thiouridine 2 -phosphorothioate (297)... 

A theoretical study based on MP2/6-31+G(d,p) and HF/6-31G(d) ab initio quantum mechanical calculations coupled with Langevin dipoles (LD) and polarised continuum (PCM) solvation models have been carried out by Florian and Warshel [387] to achieve a first systematic study of the free energy surfaces for the hydrolysis of methylphosphate in aqueous solution. The important biological implication of this work is the fact that since the energetics of both the associative and the dissociative mechanics are not too different, the active sites of enzymes can select either mechanism depending on the particular electrostatic environment. This conclusion basically means that both mechanisms should be considered, and this fact seems to contradict some previous studies which have focused on phosphoryl transfer reactions. 

Mechanism, and the source of unusual KIEs. The primary 9- N KIEs for the PNP-catalyzed reactions were anomalously low compared both to calculations and other experimental leaving group primary KIEs. The expected KIE for complete A-glycoside bond breakage would be > 1.026, the KIE for inosine hydrolysis by lU-NH. Anomalously low 9- N KIEs may arise from the strong enzyme-leaving group interactions observed in cocrystal structures of PNP with substrate, product, and inhibitor complexes. For many reactions discussed in this chapter, the primary KIEs could be modeled by BOVA or quantum mechanical analyses and were apparently... 

Standard-free-energy maps for the hydrolysis of ATP as a function of pH and bivalent cation concentration have been published. Quantum mechanical calculations show that ATP should have a tendency to adopt a folded conformation, in agreement with crystallographic data. ... 

The quantum-mechanical (CNDO/2) calculations of Van Ool and Buck (1982) on TBP structures mimicking those of cAMP have led these investigators to propose an alternative, double-displacement mechanism to that of Eckstein for beef-heart cAMP-phosphodiesterase-catalysed hydrolysis (Scheme 37c). This proposal results from comparison of TBP energies with experimental data for binding and hydrolysis of cAMP analogues. 

Azathioprine is an immunosuppressive agent which biological and biochemical activity results from its in vivio hydrolysis mediated by a nucleophUic attack on the azathioprine molecule. DFT and ab-initio approaches have been applied to model the reaction of azathioprine with a simple nucleophile i.e. hydroxide anion. Quantum mechanical methods allowed to propose a detailed mechanism for the reaction of isolated molecule of azathioprine with hydroxide anion and thus suggest the more general mechanism for the reaction of azathioprine with nucleophiles. 

One of the best syntheses of clothianidin [157], another Takeda product, starts as well from S-methyl-N-nitroisothiourea. Just as for thiamethoxam, this compound is reacted with methylamine, and with formaldehyde and propylamine, a hexahydrotriazine is built up as a protecting group to alkylate the appropriate nitrogen with 2-chloro-5-(chloromethyl)thiazole. Hydrolysis with hydrochloric acid finally gives the active agent. [ 158] Quantum mechanical calculations, NMR spectroscopic studies and X-ray analysis confirm the ( )-con-figuration of the C=N-N02 group. [137]... 

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