Glycan binding and specificity of viral influenza neuraminidases by classical molecular dynamics and replica exchange molecular dynamics simulations

Abstract

Two important glycoproteins on the influenza virus membrane, hemagglutinin (HA) and neuraminidase (NA), are relevant to virus replication. As previously reported, HA has a substrate specificity towards SIA-2,3-GAL-1,4-NAG (3SL) and SIA-2,6-GAL-1,4-NAG (6SL) glycans, while NA can cleave both types of linkages. However, the substrate binding into NA and its preference are not well understood. In this work, the glycan binding and specificity of human and avian NAs were evaluated by classical molecular dynamics (MD) simulations, whilst the conformational diversity of 3SL avian and 6SL human glycans in an unbound state was investigated by replica exchange MD simulations. The results indicated that the 3SL avian receptor fits well in the binding cavity of all NAs and does not require a conformational change for such binding compared to the flexible shape of the 6SL human receptor. From the QM/MM-GBSA binding free energy and decomposition free energy data, 6SL showed a much stronger binding towards human NAs (H1N1, H2N2 and H3N2) than to avian NAs (H5N1 and H7N9). This suggests that influenza NAs have a substrate specificity corresponding to their HA, indicating the functional balance between the two important glycoproteins. Both linkages show distinct glycan topologies when complexed with NAs, while the flexibility of torsion angles between GAL and NAG in 6SL results in the various shapes of glycan and different binding patterns. Lower conformational diversities of both glycans when bound to NA compared to the unbound state were found, and were required in order to be accommodated within the NA cavity. Communicated by Ramaswamy H. Sarma.

Molecular modeling and phylogenetic analyses highlight the role of amino acid 347 of the N1 subtype neuraminidase in influenza virus host range and interspecies adaptation

“…The N347Y substitution markedly reduced NA binding to 6S ( ΔG PB bind difference, 19.2 Kcal mol −1 ) and had weak unfavorable effect on binding to 3S (3.9 Kcal mol −1 ). This pattern generally agreed with the results of MD simulation performed using sialotrisaccharides and NAs from wild type human and avian IVs ( Phanich et al, 2019 ). Neu5Ac provided the major favorable contribution to the binding energy among the saccharide residues of the ligand, with the highest contribution in the case of 6S-NA/N complex (−16.8 Kcal mol −1 ).…”

“…X-ray analysis of NA binding to sialoglycans could not be performed for technical reasons. Therefore, molecular dynamics (MD) simulation was used to study the interactions of Neu5Ac2–3Gal- and Neu5Ac2–6Gal-containing trisaccharides with N1 NAs from H5N1 avian and H1N1 human IVs ( Raab and Tvaroska, 2011 ; Jongkon and Sangma, 2012 ; Phanich et al, 2019 ). Collectively, these studies predicted that the catalytic sites of avian-type NAs favor binding to Neu5Ac2–3Gal- over Neu5Ac2–6Gal-containing substrates, whereas human-type NAs bind both substrates.…”

Structural Basis of Specific Glucoimidazole and Mannoimidazole Binding by Os3BGlu7

“…This event was also commonly found in other protein—ligand complexes [ 63 , 64 ], as the prediction quality of these methods primarily depends on the length of simulation time, implicit solvent model, radii sets and sampling protocols [ 65 ]. To outperform the predicted binding energies for such complexes, a higher-level calculation using the QM/MM-GBSA method [ 66 ] was conducted, where the inhibitor molecule was treated as the QM region based on the SCC-DFTB semiempirical Hamiltonian. In our case, the result shows that the evaluation of the binding free energy calculated with the SCC-DFTB/MM-GBSA method is relatively improved, as compared to the conventional MM/PB(GB)SA free energy calculations, particularly for the MIm system.…”

The preparation of a boronate affinity-based controlled oriented imprinting coating on a silica nanoparticle surface for the separation and purification of shikimic acid in herbal medicine

“…It can be used as the raw material of the star drug GS4104 (Tamiflu) against the avian flu virus H7N9 3 and is one of the most effective drugs against the A (H1N1) virus. 4 It can also be used to produce harmless herbicides and antimicrobial drugs. Currently, there are three main methods of industrially producing shikimic acid for the manufacturing of oseltamivir.…”