The modulation of the acetylation state of core histones plays a pivotal role in the regulation of gene expression.Acetylation and deacetylation of histones are controlled by two corresponding enzymes,histone acetyltransferases and histone deacetylases（HDACs）. Inhibitors of histone deacetylases are well known as a new and promising class of anticancer agents.They induce growth arrest,cell differentiation and apoptosis in tumor cells.The HDACs belong to four structurally and functionally different phylogenetic classes.ClassⅠ（1, 2,3,8）,classⅡ（4-7,9,10） and classⅣ（HDAC11） are zinc dependent proteases,and the classⅢHDACs are NAD⁺ dependent enzymes.The active site of HDACs has been uncovered on the basis of the crystal structure HDLP and HDAC8.But it is far from being completely elucidated that why variant inhibitors have different inhibitory activities.The selectivity of HDACs inhibitors is also unknown.As far as the structure is concerned, cyclopeptide inhibitors have larger surface recognition cap groups,which would be important for their selectivity toward HDACs isoforms.Apicidin and its three analogues（apicidin B,apicidin C and analogue d） are all cyclopeptide HDACs inhibitors.The experimental IC₅₀ values of the four HDACs inhibitors toward HDAC1 are 1,10,6 and 86 nM,respectively,while the IC₅₀ of apicidin toward HDAC8 is above 1000 nM.In this paper,the interactions between the HDACs and their inhibitors are studied by molecular simulation.A 3D structure model of human HDAC1 is constructed based on the crystal structure of human HDAC8,and the model quality is checked by several validation tests.Furthermore,the cyclopeptides apicidin and its analogues （apicidin B,apicidin C and analogue d） are docked to the HDAC1 model and HDAC8 to analyze the possibly binding modes.Finally,molecular dynamics studies are performed on the HDAC1-apicidin and HDAC8-apicidin complexes to search their structural stability.At the entrance portion of the active pocket,there are Glu98 and Arg270 in HDAC1 instead of Tyr100 and Met274 comparing with HDAC8.This change makes the pocket entrance more open in HDAC1,indicating that those inhibitors with large cap groups might bind to the active site in a more favorable manner.The keto-carbonyl moiety of cyclopeptides chelating with zinc ion is the basis of low binding energy,which means high inhibitory activity.The analogue d contacts less residues of HDAC1 than apicidin does,which is consistent with its lower inhibitory activity(△G_binding=-8.54 kcal/mol) comparing with apicidin(△G_binding= -9.67 kcal/mol).The docking results of apicidin and HDAC8 indicate that,the cyclopeptides are apt to bind to the second cavity near the active pocket instead of coordinating with Zn²⁺. When apicidin binding to the second cavity of HDAC8,it forms less stable interactions with the enzyme and can not inhibit the acetylated sidechains of lysine of histone entering the active pocket.This could be an explanation for the selectivity of apicidin toward HDAC1 and HDAC8.The molecular dynamics simulation results shows that,the Arg270 locating at the entrance of the HDAC1 active pocket plays a crucial role in forming stable interactions with apicidin.There are two lasting hydrogen bonds between apicidin and HDAC1 during the molecular dynamics simulation,while none between apicidin and HDAC8.This difference could be another important reason for the high inhibitory activity of apicidin to HDAC1.This study would be helpful for the optimization of cyclopeptide HDAC inhibitors,especially for the design of selective HDACs inhibitors.