The molecular dynamics (MD) simulation is employed to investigate a certain enzymatic family of Sirtuin, which is related to the human silent information regulator 2. The interactive mechanism between Sirt1, Sirt2 (two members of the family of Sirtuin) and an active molecule (named INA in the present article) is studied in detail. The initial geometry of INA comes from the reference and is optimized at the B3LYP/6-311G** level. The homology modeling method is used to construct the conformation of Sirt1. Orderly, the NAD⁺ and INA are combined with the Sirt1 and Sirt2 (the initial Sirt2 conformation comes from the X-ray crystal diffraction) by using the molecular docking. In either system, the docking complex which has the lowest energy is set as the initial conformation in the next step. The MD simulations of 50 ns are carried out to optimize the two complexes of Sirt1(NAD⁺)-INA and Sirt2(NAD⁺)-INA, respectively. The MM-GBSA calculation is carried out to obtain the binding free energies between some key residues and INA. The decomposition values of binding free energies can indicate the binding sites of INA with the Sirt1(NAD⁺) and Sirt2(NAD⁺) complexes, respectively. It is located at Val72, Ser73 and Arg272 in the former and Phe235, Leu264 and Gly305 in the latter. The result of MD simulation can also indicate that the distance between INA and enzymatic substrate of NAD⁺ is longer in the Sirt2(NAD⁺)-INA than that in the Sirt1(NAD⁺)-INA complex, which leads to a weaker interaction between INA and NAD⁺in the former. Thus, the reactive activity of INA is weaker in Sirt2 than in Sirt1. The result is corresponding with that in experiment. And it is very significance to search some novel medicines which are mainly aimed at the histone acetylase of Sirt1 and Sirt2.

Key words: molecular dynamics simulation, Sirt1, Sirt2, active molecule of INA, interactive mechanism