Hemagglutinin (HA) binds to sialylated glycans exposed on the host cell surface in the initial stage of avian influenza virus infection. It has been previously hypothesized that glycan topology plays a critical role in the human adaptation of avian flu viruses, such as the potentially pandemic H5N1. Comparative molecular dynamics (MD) studies are complementary to experimental techniques including glycan microarray to understand better the mechanism of species specificity switch. The examined systems comprise explicitly solvated trimeric forms of avian H3, H5, and swine H9 in complex with avian and human glycan receptor analogs, α-2,3 linked lactoseries tetrasaccharide a (LSTa) and α-2,6 linked LSTc, respectively. The glycans adopted distinct topological profiles with inducible torsional angles when bound to different HA’s. The corresponding receptor binding domain amino acid contact profiles were also distinct. Avian H5 was able to accommodate LSTc in a tightly “folded-umbrella”-like topology through interactions with all five sugar residues. After considering conformational entropy, the relative binding free energy changes, calculated using the molecular mechanics-generalized Born surface area (MM-GBSA) technique, were in agreement with previous experimental findings, and also provided insights on electrostatic, van der Waals, desolvation and entropic contributions to HA-glycan interactions. The topology profile and the relative abundance of free glycan receptors may influence receptor binding kinetics. Glycan composition and topological changes upon binding different HA may be important determinants in species specificity switch.