Constraining the electron densities in DFT method as an effective way for ab initio studies of metal-catalyzed reactions

The use of hybrid ab initio QM/MM methods in studies of metalloenzymes and related systems presents a major challenge to computational chemists. Metho ds that include the metal ion in the quantum mechanical region should also include the ligands of the metal in this region. Such a treatment, however, should be very demanding if one is interested in performing the configurat ional averaging needed for proper calculations of activation free energies. In the present work we examine the ability of the frozen DFT (FDFT) and th e constrained DFT (CDFT) approaches to be used in nb initio studies of meta l-catalyzed reactions, while allowing for an effective QM (rather than a QM /MM) treatment of the reacting complex. These approaches allow one to treat the entire enzyme by ab initio DFT methods, while confining the SCF calcul ations to a relatively small subsystem and keeping the electron density of the rest of the system frozen (or constrained). It is found that the FDFT a nd CDFT models can reproduce the trend obtained by a full DFT calculation o f a proton transfer between two water molecules in a (Im)(3)Zn2+(H2O)(2) sy stem. This and related test cases indicate that our approximated models sho uld be capable of providing a reliable representation of the energetics of metalloenzymes. The reasons for the special efficiency of the FDFT approach are clarified, and the strategies that can be used in FDFT studies of meta lloenzymes are outlined. (C) 2000 John Wiley & Sons, Inc.