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-tra nsfer step characteristic of liver alcohol dehydrogenase is studied on the hydride-transfer reaction as modeled by a methanolate anion inter acting with a cycle propenyl cation. It is shown first that this is an adequate model by comparing it to the methanolate-pyrydinium cation m odel transition structure, (Ts). The side-chain effect is modeled firs t 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 exchan ged hydrogen has an invariant value at the rs and the reactant, while for the product, the NAC depends upon the external perturbation introd uced by the ancillary molecule (the TS is reactant-like); (ii) the pro ducts are strongly destabilized, so the (activation) barrier with resp ect to the TS diminishes; (iii) the energy gap between reactants and p roducts is sensibly diminished by the presence of methanol; (iv) the a lcoholate 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 simplifie d model, methanol appears to have a catalytic effect via hydrogen bond ing. (C) 1996 John Wiley & Sons, Inc.