Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An Ab initio QM/MM molecular dynamics study

Wenjing Gong, Ruibo Wu, Yingkai Zhang

Research output: Contribution to journalArticle

Abstract

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. Two HDAC inhibitors have been approved by FDA as anti-cancer drugs: one is SAHA whose hydroxamate is directly bound to zinc, the other is FK228 whose active form may use thiol as the zinc binding group. In spite of extensive studies, it remains to be ambiguous regarding how thiol and hydroxamate are bound to the zinc active site of HDACs. In this work, our computational approaches center on Born-Oppenheimer ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics with umbrella sampling, which allow for modeling of the zinc active site with reasonable accuracy while properly including dynamics and effects of protein environment. Meanwhile, an improved short-long effective function (SLEF2) to describe non-bonded interactions between zinc and other atoms has been employed in initial MM equilibrations. Our ab initio QM/MM MD simulations have confirmed that hydroxamate is neutral when it is bound to HDAC8, and found that thiol is deprotonated when directly bound to zinc in the HDAC active site. By comparing thiol and hydroxamate, our results elucidated the differences in their binding environment in the HDAC active sites, and emphasized the importance of the linker design to achieve more specific binding toward class IIa HDACs.

Original languageEnglish (US)
Pages (from-to)2228-2235
Number of pages8
JournalJournal of Computational Chemistry
Volume36
Issue number30
DOIs
StatePublished - Nov 1 2015

Fingerprint

Histone Deacetylases
Zinc
Sulfhydryl Compounds
Molecular Dynamics
Molecular dynamics
Cancer
MD Simulation
Ambiguous
Inhibitor
Drugs
Genes
Sampling
Gene
Proteins
Protein
Atoms
Target
Dependent
Interaction
Modeling

Keywords

  • HDAC
  • inhibitor
  • molecular dynamics
  • QM/MM
  • Zinc enzyme

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Mathematics

Cite this

Thiol versus hydroxamate as zinc binding group in HDAC inhibition : An Ab initio QM/MM molecular dynamics study. / Gong, Wenjing; Wu, Ruibo; Zhang, Yingkai.

In: Journal of Computational Chemistry, Vol. 36, No. 30, 01.11.2015, p. 2228-2235.

Research output: Contribution to journalArticle

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