Principles of glycan-nucleotide interactions revealed by binding affinities between glycans and single-stranded DNA molecules

Glycans are essential in the development of nano-delivery systems for nucleic acid drugs to improve biological stability and bioavailability for enhanced therapeutic efficacy. It is of genuine interests to explore the principles of interactions between glycans and nucleic acids for designing and formulation of nano-delivery systems for nucleic acids. In this study, we endeavored to explore general principles of the binding strengths between 19 glycans and nucleotides of adenine, thymine, guanine and cytosine in homogeneous single-stranded DNAs (ssDNAs). Using a microbead-based fluorescence assay, we measured the binding affinities of surface-immobilized glycans interacting with ssDNA in solution. Comparative analyses of the measured distributions binding energy reveal unique interaction strength patterns assignable to each DNA nucleotide and glycan originating from the chemical structures. The obtained results also reveal that hydrogen bonds dominate the interactions between ssDNA and glycans, while electrostatic interactions, molecular weight and glycan structures also contribute to the interactions. The molecular insights of the selectivity, specificity and polymorphism in glycan-nucleotide interactions observed in this work could provide the basis for design and formulation of nano-delivery systems for nucleic acid drugs, as well as understanding the biological properties relating to glycosylation of nucleic acids.