Modeling the effect of Zn(II) on the hydrogen transfer in inhibition processes

Abstract

We present in this work the results of a rather simplified theoretical approach to some of the processes involved in the inhibition of Zn-containing active sites. Our aim is to calibrate a model in which Zn is replaced by Be. The motivation for this strategy is to provide a qualitatively correct, but fast, approach that can be used in the simulation of many inhibitors interacting with a Zn site. The use of Be allows us to retain some of the essential features of the inhibitor–Zn interaction, while involving much less computation time. It should be noted that we are not modeling a Be-containing active site, but processes occurring in a Zn-containing one. We design a scaling transformation that permits us to relate the electronic properties associated with a given Be–ligand distance to the same electronic properties associated with a desired Zn–ligand distance. The results provided by the Be-containing model are comparable to those corresponding to the actual Zn-containing model. One of the processes we are interested in describing here is the effect that the presence of a Zn(II) cation has on the ability of an inhibitor to donate a proton to an acceptor. This process is of importance in the inhibition of Zn-containing enzymes, such as liver alcohol dehydrogenase (LADH). The inhibitory mechanism of LADH seems to involve first the interaction of a ligand with the Zn cation, followed by the transfer of a proton to an acceptor, and finally the binding of the deprotonated ligand to the nicotinamide adenine dinucleotide (NAD+) coenzyme. In this work, we considered the molecule of formaldehydehydrazone as a model of an inhibitor (e.g., pyrazole). This simplified model contains the strict essentials needed to study proton transfer mediated by a metallic cation. We found a parallelism between the roles of the two metals in the H transfer from this model of inhibitor that allows us to make some qualitative predictions for other processes in Zn from the results obtained exclusively in the presence of Be.