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.

Public Health Relevance

Zinc proteins play essential roles in many biological processes, and their malfunctioning or aberrant over-expression has been mechanistically linked to a variety of diseases. Several key zinc proteins have been established as attractive drug targets, including matrix metalloproteinases (MMPs), histone deacetylases (HDACs) and tumor suppressor protein P53. Our proposed studies would significantly advance the field of structure, dynamics and functional studies of zinc metalloproteins, and facilitate the design of new inhibitors for medically important zinc enzymes which can serve as novel drug candidates and innovative chemical probes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Schools of Arts and Sciences
New York
United States
Zip Code
Gong, Wenjing; Wu, Ruibo; Zhang, Yingkai (2015) Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study. J Comput Chem 36:2228-35
Zhou, Jingwei; Li, Min; Chen, Nanhao et al. (2015) Computational design of a time-dependent histone deacetylase 2 selective inhibitor. ACS Chem Biol 10:687-92
Zhou, Nengjie; Lu, Zhenyu; Wu, Qin et al. (2014) Improved parameterization of interatomic potentials for rare gas dimers with density-based energy decomposition analysis. J Chem Phys 140:214117
Rooklin, David W; Lu, Min; Zhang, Yingkai (2012) Revelation of a catalytic calcium-binding site elucidates unusual metal dependence of a human apyrase. J Am Chem Soc 134:15595-603