title: Sirtuin Deacetylation Mechanism and Catalytic Role of the Dynamic Cofactor Binding Loop.
abstract: 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-Oppenheimerab initioQM/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 would facilitate the design of novel mechanism-based sirtuin modulators.
authors.affiliation: Department of Chemistry, New York University, New York, New York 10003.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Shi
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shenglong
authors.initials: S
authors.lastname: Wang
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Zhang
keywords: ab initio QM/MM molecular dynamics simulation; enzyme catalysis; free energy and umbrella sampling; protein deacetylation; reaction mechanisms