Background: Recognition of terminal sialyldisaccharides by influenza A hemagglutinin initiates the infection process of influenza. Results: MD simulations on sialyldisaccharide-hemagglutinin (H1, H3, H5, and H9) complexes reveal the molecular basis of specific recognition. Conclusion:The order of the binding specificity of Neu5Ac␣(2-3)Gal and Neu5Ac␣(2-6)Gal is H3 Ͼ H5 Ͼ H9 Ͼ H1 and H1 Ͼ H3 Ͼ H5 Ͼ H9, respectively. Significance: The insights from this study will help in designing carbohydrate-based therapeutics against influenza viral infections.

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Wheat germ agglutinin (WGA) is a plant lectin, which specifically recognizes the sugars NeuNAc and GlcNAc. Mutated WGA with enhanced binding specificity can be used as biomarkers for cancer. In silico mutations are performed at the active site of WGA to enhance the binding specificity towards sialylglycans, and molecular dynamics simulations of 20 ns are carried out for wild type and mutated WGAs (WGA1, WGA2, and WGA3) in complex with sialylgalactose to examine the change in binding specificity. MD simulations reveal the change in binding specificity of wild type and mutated WGAs towards sialylgalactose and bound conformational flexibility of sialylgalactose. The mutated polar amino acid residues Asn114 (S114N), Lys118 (G118K), and Arg118 (G118R) make direct and water mediated hydrogen bonds and hydrophobic interactions with sialylgalactose. An analysis of possible hydrogen bonds, hydrophobic interactions, total pair wise interaction energy between active site residues and sialylgalactose and MM-PBSA free energy calculation reveals the plausible binding modes and the role of water in stabilizing different binding modes. An interesting observation is that the binding specificity of mutated WGAs (cyborg lectin) towards sialylgalactose is found to be higher in double point mutation (WGA3). One of the substituted residues Arg118 plays a crucial role in sugar binding. Based on the interactions and energy calculations, it is concluded that the order of binding specificity of WGAs towards sialylgalactose is WGA3 > WGA1 > WGA2 > WGA. On comparing with the wild type, double point mutated WGA (WGA3) exhibits increased specificity towards sialylgalactose, and thus, it can be effectively used in targeted drug delivery and as biological cell marker in cancer therapeutics.

The results obtained in the present work provide deep insights for understanding the interplay between stability and binding in protein-carbohydrate complexes.

Sialyldisaccharides are significant terminal components of glycoconjugates and their negative charge and conformation are extensively utilized in molecular recognition processes. The conformation and flexibility of four biologically important sialyldisaccharides [Neu5Acα(2-3)Gal, Neu5Acα(2-6)Gal, Neu5Acα(2-8)Neu5Ac and Neu5Acα(2-9)Neu5Ac] are studied using Molecular Dynamics simulations of 20 ns duration to deduce the conformational preferences of the sialyldisaccharides and the interactions which stabilize the conformations. This study clearly describes the possible conformational models of sialyldisaccharides deduced from 20 ns Molecular Dynamics simulations and our results confirm the role of water in the structural stabilization of sialyldisaccharides. An extensive analysis on the sialyldisaccharide structures available in PDB also confirms the conformational regions found by experiments are detected in MD simulations of 20 ns duration. The three dimensional structural coordinates for all the MD derived sialyldisaccharide conformations are deposited in the 3DSDSCAR database and these conformational models will be useful for glycobiologists and biotechnologists to understand the biological functions of sialic acid containing glycoconjugates.