Our long term goal is to develop and apply computational methods to provide novel mechanistic insights into catalysis and regulation of histone modifying enzymes, and to facilitate the rational design of enzyme sub-type specific modulators for probing epigenetic pathways and therapeutic use. Reversible histone acetylation has emerged as a vital regulator in a multitude of essential epigenetic processes. The enzymes responsible for this essential post-translational modification are histone acetyl transferases (HATs) and histone deacetylases (HDACs) that add and remove acetyl groups to and from target lysine residues, respectively. The aberrant activity of these enzymes has been implicated in numerous human diseases, notably cancer, and quite a few HATs and HDACs have been established as important drug targets. Our theoretical approaches will center on Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, a state-of-the-art computational approach to simulate enzyme reactions which allow for accurate modeling of the chemistry at the enzyme active site while properly including dynamics and effects of protein environment.
The specific aims are: 1. Characterize the catalytic mechanism for HATs and rational redesign of tGcn5 for its improved efficiency.
Aim 2 : Elucidate inner workings of sirtuins, a novel family o class III histone deacetylases.
Aim 3 : Advance ab initio QM/MM methods. The successful completion of the proposed research will provide a detailed mechanistic understanding for HATs and sirtuins for the first time. This will stimulate further mechanistic studies of these important enzymes, and facilitate the development of novel mechanism-based modulators for probing acetylation dependent epigenetic pathways and for therapeutic use. Meanwhile, our methodology development efforts will significantly advance this computational tour de force to simulate enzyme reactions, and help establish it as an equal partner to experimental approaches in this important field of enzymology.

Public Health Relevance

Histone modifying enzymes have emerged as vital regulators in cellular processes. The aberrant activity of these enzymes has been implicated in numerous human diseases, notably cancer, and quite some HATs and HDACs have been established as important drug targets. To elucidate their inner workings will facilitate the development of new drugs to cure these diseases. Meanwhile, we will develop more powerful methods for the computational biomedical research.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter C
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New York University
Schools of Arts and Sciences
New York
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Zhou, Yanzi; Xie, Daiqian; Zhang, Yingkai (2016) Amide Rotation Hindrance Predicts Proteolytic Resistance of Cystine-Knot Peptides. J Phys Chem Lett 7:1138-42
Fu, Iwen; Cai, Yuqin; Zhang, Yingkai et al. (2016) Entrapment of a Histone Tail by a DNA Lesion in a Nucleosome Suggests the Lesion Impacts Epigenetic Marking: A Molecular Dynamics Study. Biochemistry 55:239-42
Hou, Xuben; Rooklin, David; Fang, Hao et al. (2016) Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation. Sci Rep 6:38186
Zhou, Y; Wang, S; Li, Y et al. (2016) Born-Oppenheimer Ab Initio QM/MM Molecular Dynamics Simulations of Enzyme Reactions. Methods Enzymol 577:105-18
Lei, Jinping; Zhou, Yanzi; Xie, Daiqian et al. (2015) Mechanistic insights into a classic wonder drug--aspirin. J Am Chem Soc 137:70-3
Rooklin, David; Wang, Cheng; Katigbak, Joseph et al. (2015) AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein-Protein Interaction Interfaces. J Chem Inf Model 55:1585-99
Mu, Hong; Geacintov, Nicholas E; Zhang, Yingkai et al. (2015) Recognition of Damaged DNA for Nucleotide Excision Repair: A Correlated Motion Mechanism with a Mismatched cis-syn Thymine Dimer Lesion. Biochemistry 54:5263-7
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
Sirin, Gulseher Sarah; Zhang, Yingkai (2014) How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study. J Phys Chem A 118:9132-9

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