Zinc Chelation with Hydroxamate in Histone Deacetylases Modulated by Water Access to the Linker Binding Channel
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It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylase (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity has been revealed but is not understood. Using Born-Oppenheimer ab initio QM/MM MD simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggest a novel mechanism in which the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes its importance and gives guidance regarding linker design for the development of new class-IIa-specific HDAC inhibitors.
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Spherical potentials are especially suitable for accurately reproducing hydroxamate coordination geometries.
“Spherical potentials are particularly suitable for accurately reproducing hydroxamate coordination geometries.39,40”
From AutoDock4<sub>Zn</sub>: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins (2014) · cites this paper as [39]
The paper’s discussion of QM/MM simulations says they reproduced hydroxamate coordination configurations in HDAC8 and HDAC7, but it does not identify spherical potentials as the method responsible. Searches for spherical potentials and their suitability for reproducing coordination geometry found no passage addressing that claim (page unavailable in our copy). (LLM, conf=0.73)
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- Authors
- Wu, R., Lu, Z., Cao, Z., & Zhang, Y.
- Affiliations
- Xiamen University (CN)
- New York University (US)
- Corresponding author
- Cao, Zexing
- Zhang, Yingkai
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-04-01
- Volume
- 133
- Issue
- 16
- Pages
- 6110-6113
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC3086135
- OpenAlex
- W1988811573
- Cited by
- 108
- References
- 39
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 9 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 15 · 2013: 8 · 2012: 7
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM079223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- histone deacetylase, HDAC8, zinc chelation, hydroxamate, water access, isoform-selective inhibitors
- MeSH terms
- Chelating Agents, Histone Deacetylases, Hydrogen Bonding, Hydroxamic Acids, Quantum Theory, Water, Zinc
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