This proposal is directed at developing novel transferable non-bonded force fields to model zinc metalloproteins and to design zinc enzyme inhibitors. Zinc proteins play essential roles in many biological processes, and there is an increasing appreciation of their biological and medical importance. For example, zinc-dependent histone deacetylases (HDACs) play a critical role in transcriptional repression and gene silencing, and are among the most attractive targets for the development of new therapeutics against cancer and various other diseases. Thus, robust computational approaches are greatly needed to help characterize the structure and dynamics of zinc metalloproteins, and to facilitate the design and ranking of zinc enzyme inhibitors. However, progress along this direction has been very much impeded mainly due to the lack of transferable pairwise force fields to adequately describe zinc coordination. The current dominant view is that such a force field may not be possible and that it would be necessary to go beyond the pairwise non-bonded model for reasonable description of the zinc coordination. In our preliminary studies, we have discovered a novel practical strategy to overcome this inherent challenge, which is to design short-long effective functions (SLEF) to treat electrostatic interactions between the zinc ion and all other atoms. Our preliminary results indicated that this SLEF approach is very promising to adequately model flexible zinc coordination. Here we propose to develop SLEF force fields to simulate zinc metalloproteins, and to develop SLEF scoring functions for docking ligands into zinc enzymes. The developed SLEF patches to the AMBER and Autodock softwares as well as tutorials and test sets will be made freely available to the public.