Abstract
All cells are decorated with a highly dense and complex structure of glycan chains, which are mostly attached to proteins and lipids. In this context, sialic acids are a family of nine-carbon acidic monosaccharides typically found at the terminal position of glycan chains, modulating several physiological and pathological processes. Sialic acids have many structural and modulatory roles due to their negative charge and hydrophilicity. In addition, the recognition of sialic acid glycans by mammalian cell lectins, such as siglecs, has been described as an important immunological checkpoint. Furthermore, sialic acid glycans also play a pivotal role in host–pathogen interactions. Various pathogen receptors exposed on the surface of viruses and bacteria are responsible for the binding to sialic acid sugars located on the surface of host cells, becoming a critical point of contact in the infection process. Understanding the molecular mechanism of sialic acid glycans recognition by sialic acid-binding proteins, present on the surface of pathogens or human cells, is essential to realize the biological mechanism of these events and paves the way for the rational development of strategies to modulate sialic acid-protein interactions in diseases. In this perspective, nuclear magnetic resonance (NMR) spectroscopy, assisted with molecular modeling protocols, is a versatile and powerful technique to investigate the structural and dynamic aspects of glycoconjugates and their interactions in solution at the atomic level. NMR provides the corresponding ligand and protein epitopes, essential for designing and developing potential glycan-based therapies. In this review, we critically discuss the current state of knowledge about the structural features behind the molecular recognition of sialic acid glycans by different receptors, naturally present on human cells or pathogens, disclosed by NMR spectroscopy and molecular modeling protocols.
Highlights
Sialic acids are nine-carbon monosaccharides constituted by a carboxylate group (C1) attached to a quaternary anomeric carbon (C2), a deoxygenated C3, an exocyclic 3-carbon glycerol side chain at C6, and different substituents at C5 (Figure 1A) (Schnaar et al, 2014; Varki et al, 2015)
The specificity of these molecular recognition events is modulated by the conformation of the sialoglycan, which strongly influences the presentation of the Neu5Ac residue to the receptor, and by additional interactions established by other sugar residues and functional groups present in the sialoglycan and in the receptor (Veluraja et al, 2010)
nuclear magnetic resonance (NMR) spectroscopy assisted with computational methods has proved to be a powerful and robust methodology to disentangle the conformations of sialic acid oligosaccharides in solution, as well as to unveil the molecular determinants that govern the interactions between sialic acids and receptors
Summary
Sialic acids are nine-carbon monosaccharides constituted by a carboxylate group (C1) attached to a quaternary anomeric carbon (C2), a deoxygenated C3, an exocyclic 3-carbon glycerol side chain at C6, and different substituents at C5 (Figure 1A) (Schnaar et al, 2014; Varki et al, 2015). NMR spectroscopy assisted with computational methods (such as molecular mechanics, molecular dynamics, and Monte Carlo simulation) has proved to be a powerful and robust methodology to disentangle the conformations of sialic acid oligosaccharides in solution, as well as to unveil the molecular determinants that govern the interactions between sialic acids and receptors In this context, the present review is focused on the current knowledge of Neu5Ac-based sialoglycan’s conformation (Conformation of Neu5Ac Sialoglycans in Solution), together with their binding mechanisms to different receptors, naturally present in human cells (siglecs—Sialic Acid–Siglec Interactions) and on pathogens, namely, viruses (Sialic Acid–Virus Interactions) and bacteria (Sialic Acid–Bacteria Interactions), mainly disclosed by NMR spectroscopy and molecular modeling protocols. Neu5Ac can be attached to a galactose (Gal) residue through the α2,3-linkage, described by the φ (C1-C2-O-C3′) and ψ (C2-O-C3′-H3′) torsion angles; to a Gal, a N-acetylgalactosamine (GalNAc), or a N-acetylglucosamine (GlcNAc) residue by an α2,6-linkage, characterized by φ (C1-C2O-C6′), ψ (C2-O-C6′-C5′), and ω (O-C6′-C5′-O5′) torsion angles; or to another sialic acid, through an α2,8-linkage defined by the torsion angles φ (C1-C2-O-C8′), ψ (C2O-C8′-C7′), ω9 (O9′-C9′-C8′-O), ω8 (O8′-C8′-C7′-O7′), and ω7 (O7′-C7′-C6′-O6′)
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