Boronate-Diol Interactions in Membranes: A Biomimetic Tool for Polysaccharide Recognition

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Abstract

Molecular recognition at biomembranes is one of the more poorly understood aspects of fundamental research in physical organic chemistry. Our aim was to improve our understanding of the molecular recognition of polysaccharides at biomembranes, in particular developing synthetic lipids that will recognise and report on the presence of glycosaminoglycans (GAG polysaccharides), like heparin and hyaluronic acid. Elevated levels of hyaluronic acid have been implicated in bladder carcinoma and osteoarthritis, and the use of heparin for medical applications is well documented. We synthesised a boronic acid capped lipid that also bore a fluorinated fluorescent reporter group, which could report on multivalent recognition events at bilayer membranes by fluorescent quenching and changes in the lateral distribution of the reporter groups. These preliminary studies showed these boronic acid capped fluorinated lipids gave a fluorescent signal upon interaction with simple mono- and poly- saccharides, albeit with unexpectedly weak binding to these saccharides. To understand and quantify the weaker binding of saccharides to membrane bound boronic acids a series of novel fluorescent and chromogenic lipids were synthesised that bore the reporter group close to the boronic acid. These studies revealed several underlying factors that had important roles in the recognition of oligosaccharides by boronic acid capped lipids. For the first time the effect of the bilayer on saccharide/boronic acid recognition was quantified, with the membrane weakening the interaction 33-fold. We were able to propose a model for the interaction of saccharides for membrane bound boronic acids that explained many of these unexpected observations.We also devised a parallel approach using GAGs to open or close synthetic membrane channels. Using a GAG to switch on the release of an ion or dye would generate a fluorescent signal that amplifies the original recognition event and improves sensitivity for GAGs. Proof-of-principle studies using palladium ions to open dye-transporting channels were successful and these studies were followed by the synthesis of boronic acid-capped cholates. Incorporation of boronic acid-capped cholates into membranes caused changes in the rate of release of alkali metal ions, which caused an enclosed fluorescent dye to give a signal, in the presence or absence of saccharides. These compounds successfully gave a response to the simple saccharide D-fructose but gave no response to other saccharides tested, including various hyaluronic acids. Although we were not able to develop a selective sensor for GAGs, we have developed a model for saccharide/boronic acid interactions that is a valuable addition to the physical organic chemistry of membranes.

Keyword(s)

Biomembranes; Boronic acids; Ion Transport; Ionophore; Molecular Recognition; Saccharides

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