On a possible invariance of a transition structure to the effects produced by ancillary H-bonding molecules: Modeling the effects of Ser-48 in the hydride-transfer step of liver alcohol dehydrogenase

The influence of a hydroxyl group simulating Ser-48 in the hydride-transfer step characteristic of liver alcohol dehydrogenase is studied on the hydride-transfer reaction as modeled by a methanolate anion interacting with a cyclo propenyl cation. It is shown first that this is an adequate model by comparing it to the methanolate-pyrydinium cation model transition structure, (TS). The side-chain effect is modeled first by adding water and then with methanol located at the position that Ser-48 occupies in the enzyme; a supermolecule approach is used. It is found that (i) the normalized advance coordinate (NAC) for the exchanged hydrogen has an invariant value at the TS and the reactant, while for the product, the NAC depends upon the external perturbation introduced by the ancillary molecule (the TS is reactant-like); (ii) the products are strongly destabilized, so the (activation) barrier with respect to the TS diminishes; (iii) the energy gap between reactants and products is sensibly diminished by the presence of methanol; (iv) the alcoholate moiety in the hydride transfer complex is not spontaneously protonated; and (v) there is a negligible charge transfer between the hydride-transfer system and models of Ser-48. In the present simplified model, methanol appears to have a catalytic effect via hydrogen bonding. © 1996 John Wiley & Sons, Inc.