Entropy trap

Designing haptens in order to stimulate the production of catalytic antibodies depends on a variety of strategies based on transition state analogs, entropy traps and opportunistic chemistry. 

Furthermore, antibodies should be capable of efficiently catalyze reactions with unfavorable entropies of activation by acting as entropy traps the binding energy of the antibody being used to freeze out the rotational and translational degrees of freedom necessary to form the activated complex. This principle has been applied to the design of antibodies that catalyze both unimolecular and bimolecular reactions (see below). 

The antibodies can also act like entropy traps by stabilizing a particular conformation of a substrate that is favorable to the formation of the TS. It is the case of the antibody 1F7 catalyzing the transformation of chorismate into prephenate," which stabilizes, thanks to several hydrogen bonds and an ionic bond between an arginine (Arg H95) and a carboxylate substituent of the substrate, the conformation of the chorismate which will give rise to the TS in a chair conformation for this reaction (Figure 11). 

ENTROPY TRAP MODEL MOLECULAR SIMILARITY TRANSITION-STATE INHIBITORS pCa pD... 

Besides the stabilization of charged transition states, the effect as entropy traps is decisive for the effect as a catalyst. Entropy trap refers to the ability of a catalyst to bind substrates in a favorable orientation and thus to freeze out translational and rotational degrees of freedom of the substrate (Chapter 2, Section 2.2.3). The result corresponds to a drastic increase in the effective molarity of the substrate, to a concentration level which can never be reached in free solution. The transesterification reaction in Figure 18.5 (Schultz, 1993) would be difficult to conduct in water under ordinary circumstances as the hydrolysis side reaction is aided by a water concentration of 55.5 m. A comparison of kcM/KM [(m s) x] with the uncatalyzed reaction in water [s-1] (strictly speaking, [H20] at 55.5 m has to be considered as well, so a dimension of [(m s) 11 again results) yields an effective molarity of 106 m. 

Figure 18.5 Transesterification reaction with entropy trap (Schultz, 1993).

The reaction, which proceeds via a conformationally tight chair-type transition state, is clearly entropically dominated, with a AS of -13 eu. Whereas the known enzyme chorismate mutase from E. coli achieves a 3 x 106-fold accelerated catalysis, the antibody reaches a 104-fold enhancement. A decrease of AS to almost 0 eu points to the presence of an entropy trap. 

Kast P, M Asif-Ullah, D Hilvert (1996) Is chorismate mutase a prototypic entropy trap Activation parameters for die Bacillus subtilis enzyme. Tetrahedron Lett. 37 (16) 2691—2694... 

Kati, W. M., Wolfenden, R. Contribution of a single hydroxyl group to transition-state discrimination by adenosine deaminase evidence for an entropy trap mechanism. Biochemistry 1989, 28, 7919-7927. 

The Diels-Alder reaction usually does not require a catalyst, and therefore, rate acceleration may be achieved by stabilizing the transition state. In fact, antibodies elicited by transition state analog are able to catalyze Diels-Alder reactions. The Diels-Alderase antibodies provide a pocket acting as an entropy trap. Using this strategy several Diels-Alderase antibodies have been created to date. " Product inhibition is an inherent problem in the use of Diels-Alderase antibodies because of the resemblance between the product and the transition state. 

The influence of the hydrophobic effect on the aqueous pericychc reactions can be compared with the effect of catalytic antibodies. Antibodies have been found to catalyze Diels-Alder reactions, hetero-Diels-Alder reactions, and Claisen and oxy-Cope rearrangements. It is suggested that antibodies catalyze these reactions by acting as an entropy trap, primarily through binding and orienting the substrates in the cyclic conformations. 

Figure 11.19 Diels-Alder reaction catalyzed by entropy trap antibody Hexachloronorbonrnene that mimics the expected transition state is used as hapten (shown under the transition state) to elicit the antibody which effectively catalyzes the bimolecular...

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