Sirtuin deacetylation mechanism and catalytic role of the dynamic cofactor binding loop

Yawei Shi, Yanzi Zhou, Shenglong Wang, Yingkai Zhang

Research output: Contribution to journalArticlepeer-review


Sirtuins constitute a novel family of protein deacetylases and play critical roles in epigenetics, cell death, and metabolism. In spite of numerous experimental studies, the key and most complicated stage of its NAD +-dependent catalytic mechanism remains to be elusive. Herein, by employing Born-Oppenheimer ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, a state-of-the-art computational approach to study enzyme reactions, we have characterized the complete deacetylation mechanism for a sirtuin enzyme, determined its multistep free-energy reaction profile, and elucidated essential catalytic roles of the conserved dynamic cofactor binding loop. These new detailed mechanistic insights could facilitate the design of novel mechanism-based sirtuin modulators.

Original languageEnglish (US)
Pages (from-to)491-495
Number of pages5
JournalJournal of Physical Chemistry Letters
Issue number3
StatePublished - Feb 7 2013


  • ab initio QM/MM molecular dynamics simulation
  • enzyme catalysis
  • free energy and umbrella sampling
  • protein deacetylation
  • reaction mechanisms

ASJC Scopus subject areas

  • General Materials Science
  • Physical and Theoretical Chemistry


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