Differential Transition State Stabilization

Szefczyk B, Mulholland AJ, Ranaghan KE, Sokalski WA (2004) Differential transition-state stabilization in enzyme catalysis Quantum chemical analysis of interactions in the chorismate mutase reaction and prediction of the optimal catalytic field. J Am Chem Soc 126 16148—16159... 

Already in 1948 Linus Pauling has put forward hypothesis 34,35] that catalytic activity of enzymes is due to transition state stabilization by enzyme active site. Extending this idea to the relative stabilization of transition state with respect to initial enzyme - substrate complex, one may obtain Differential Transition State Stabilization (DTSS) model [7], with activation barrier change A representing quantitatively the catalytic activity of any catalyst C... 

Electrostatic Differential Transition State Stabilization energies resulting from aminoacid... 

QM/MM methods have proved their value for enzyme reactions in differentiating between alternative proposed mechanisms, and in analysing contributions to catalysis. A current example is the analysis of the contribution of conformational effects and transition state stabilization in the reaction catalysed by the enzyme chorismate mutase.98,99 QM/MM calculations can be performed with... 

In order to bypass the problem of designing a pocket from scratch, Bolon and Mayo [27] introduced a catalytically active His residue in thioredoxin, a well-defined 108-residue protein for which much structural and functional information was available. The design was based on the well-known reaction mechanism of p-nitrophenyl acetate hydrolysis and thioredoxin was redesigned by computation to accommodate a histidine with an acylated side chain to mimic transition state stabilization. The thioredoxin mutant was catalytically active and the reaction followed saturation kinetics with a k at of 4.6 x 10 s and a Km of 170 xM. The catalytic efficiency, after correction for differential protonation and nucleophilicity, can be estimated to be a factor of 50 greater than that of 4-methylimidazole, due to nucleophilic catalysis and proximity effects, see Section 5.2.3. 

Differential transition state/product stabilization approach... 

FIGURE 10 6 Confor mations and electron delo calization in 1 3 butadiene The s CIS and the s trans con formations permit the 2p or bitalsto be aligned parallel to one another for maxi mum TT electron delocaliza tion The s trans conformation is more stable than the s CIS Stabilization resulting from tt electron de localization is least in the perpendicular conformation which IS a transition state for rotation about the C 2—C 3 single bond The green and yellow colors are meant to differentiate the orbitals and do not indicate their phases... 

When the carbonyl groups are present, the transition state for syn attack is sta-bihzed by interactions between the in-phase combination of the NN lone pairs and the antisymmetric n orbital of the CO-X-CO bridge (100). Although the secondary effect (SOI) operates only during syn approach and contributes added stabilization to this transition state, the primary orbital interaction (see 103) between the HOMO of the cyclohexadiene moiety of 100 and the n orbital of the dienophile (NN, Fig. 16) is differentiated with respect to the direction of attack, i.e., syn or anti, of triazolinedione (NN, Fig. 16). 

In summary, there now exists a body of data for the reactions of carbocations where the values of kjkp span a range of > 106-fold (Table 1). This requires that variations in the substituents at a cationic center result in a >8 kcal mol-1 differential stabilization of the transition states for nucleophile addition and proton transfer which have not yet been fully rationalized. We discuss in this review the explanations for the large changes in the rate constant ratio for partitioning of carbocations between reaction with Bronsted and Lewis bases that sometimes result from apparently small changes in carbocation structure. 

Based on the triglyme theozyme, additional catalysts were designed.1181 Of the potential catalysts examined, 6 was predicted to provide the best differential stabilization of the reactants and transition state. This molecule contains a polyether substructure as well as an additional hydrogen bond donor (the carbamate NH) which may further promote departure of the aryloxide leaving group. In addition, this catalyst is preorganized such that its polyether array is predisposed towards efficient... 

Ionic reactions of neutral substrates can show large solvent dependence, due to the differential solvent stabilization of the ionic intermediates and their associated dipolar transition states (Reichardt, 1988). This is the case for the electrophilic addition of bromine to alkenes (Ruasse, 1990, 1992 Ruasse et al., 1991) and the bromination of phenol (Tee and Bennett, 1988a), both of which have Grunwald-Winstein m values approximately equal to 1 so that the reactions are very much slower in media less polar than water. Such processes, therefore, would be expected to be retarded or even inhibited by CDs for two reasons (a) the formation of complexes with the CD lowers the free concentrations of the reactants and (b) slower reaction within the microenvironment of the less polar CD cavity (if it were sterically possible). 

In all of these compounds solvolysis will lead to a tertiary ion. The series [10], [13], [11] clearly indicates the strain argument, and one may note that the difference in rates between [1] and [11] corresponds to an energy difference of only 1 1 kcal mole . The data do not prove that non-classical stabilization of the transition state in [1] and [12] is not partly responsible for the rate differences but rather suggests that relief of striiin could account for the results. Other factors, particularly differential solvation of the ground state and transition state and the possibility that solvolysis may not be of a limiting type but involve reaction with solvent, may also play a role but are difficult to evaluate. In any case the rate of solvolysis of exo-compounds does not appear to be unusually rapid when viewed in this light. 

While the Sn2 reaction represents an extreme case, it is clear that the solvent is capable of selectively stabilizing (or destabilizing) one product over another in a thermodynamically-controlled reaction, or one transition state over another in a kinetically-controlled reaction. Differentiation might be effected by steric and/or electronic considerations. 

Supramolecular control of reactivity and catalysis is among the most important functions in supramolecular chemistry. Since catalysis arises from a differential binding between transition and reactant states, a supramolecular catalyst is, in essence, chemical machinery in which a fraction of the available binding energy arising from noncovalent interactions is utilized for specific stabilization of the transition state or, in other words, is transformed into catalysis. 

Cacciapaglia, R., van Doom, A.R., Mandolini, L., Reinhoudt, D.N. and Verboom, W. (1992) Differential metal ion stabilization of reactants and transition states in the transacylation of crown ether aryl acetates./. Am. Chem. Soc.. 114, 2611. 

The protein tyrosine phosphatases also exist as several families with numerous functions in control of transcription, growth, differentiation, and metabolism.741-743 These enzymes function by a doubledisplacement mechanism, as in Eq. 12-38, but with a cysteine side chain rather than serine. The cysteine is present in the conserved sequence (H/V)CX5R(S/T). The arginine binds the phospho group and helps to stabilize the transition state, which probably is metaphosphate-like.742... 

Apparently, the discrepancies detected for the substitution data are largely the consequence of a multiplicity of minor influences operative in the transition state. The deviations are sufficiently diverse in character to require the significance of additional influences on the stability of the transition state. Four other important factors are complexing of the substituent with the electrophilic reagent or catalyst, the involvement of 7r-complex character in the transition state for the reaction, rate effects originating in the rupture of carbon-hydrogen bonds, and differential solvation of the electron-deficient transition states. 

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