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

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.