Distinct Glycan Topology for Avian and Human Sialopentasaccharide Receptor Analogues upon Binding Different Hemagglutinins: A Molecular Dynamics Perspective

Abstract

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.

Influenza virus binds its host cell using multiple dynamic interactions

“…MD simulations provide detailed information on the molecular structures and unbinding pathways that govern the interaction forces. In free simulations we observed that each receptor takes a slightly different conformation, although hydrogen bonds between four HA residues (Tyr98, Gly135, Ser136, and Asn137) and the receptor were always present, which is consistent with previous simulations (21,22). These four amino acids belong to the base and loop 130 of the HA receptor-binding pocket and are highly important for binding to the receptor (1).…”

“…These differences cannot be observed with experimental force spectroscopy, where single force peaks were detected during unbinding. It was shown previously that unbound LSTc in solution adopts multiple conformations, which are strongly reduced upon binding to HA (22). This intrinsic structural variability of the receptor is also present in our unbinding simulations.…”

Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak

“…Computational modeling simulations predict RDB-receptor complexes in which the guanidinium group of R189 contacts human SA-receptor analogs through hydrogen bonds with the axial hydroxyls of the carbohydrate moiety in the fifth position. In contrast, Q189 is not found to interact with LSTc, and to our knowledge this position has not been observed experimentally (31,32,34) or through extensive molecular dynamic simulations with other HA subtypes (49) to make significant contacts with human receptors. In the predicted complexes, the Q189R side chain is remote from receptor-binding interactions that have been proposed to be important for binding receptors with α2-3 linkages.…”

Receptor Specificity of Influenza A H3N2 Viruses Isolated in Mammalian Cells and Embryonated Chicken Eggs

“…Human H3N2 viruses isolated in cell culture were reported to bind with a high affinity to ␣2-6-linked sialosides, while viruses isolated in eggs often had increased specificity for ␣2-3-linked sialosides (19,20,28). The functional classification of avian and mammalian influenza virus receptors is further complicated since in vitro and tissue-binding assays have led to new working hypotheses involving glycan chain length, topology, and the composition of the inner fragments of the carbohydrate chain as additional receptor specificity determinants (9,17,65,66,82). However, the significance of these in vitro properties remains unknown, since the structures of the natural sialosides on host cells that are used for infectious virus entry are undefined.…”