The human pathogen, Entamoeba histolytica contains four Sir2 homologs in its genome. We have designed the 3D tertiary structure of EhSir2a and its interacting partners by comparative homology modeling and studied their interaction by molecular docking. Sir2 proteins are known to interact with their substrates through the deacetylase domain present in its C-terminus. Interestingly, EhSir2a contains a unique Zn finger domain at its N terminus and this is not present in any known Sir2 protein. This study shows that EhSir2a may interact with this N-terminal residue also. It interacts with its substrate, elongation factor EhEF2 through this zinc-finger domain. The interaction sites are different for alpha-tubulin homologs, the other substrates of EhSir2a identified by yeast two-hybrid library screening. The coordinate files of the best-modeled structure for EhSir2a and its interacting proteins were processed for protein-protein docking using ClusPro v2.0 and HawkDock server. Tyr432, Asn422, Arg408 residues of α-tubulin are essential for interaction with EhSir2a. Here we report that molecular interactions of EhSir2a with its interacting partners are not restricted to the conserved NAD+ dependent deacetylase domain; it may also involve the N-terminal residue.