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Sirtuin Deacetylation Mechanism and Catalytic Role of the Dynamic Cofactor Binding Loop

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journal contribution
posted on 16.12.2015 by Yawei Shi, Yanzi Zhou, Shenglong Wang, Yingkai Zhang
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.