Hyaluronan is a natural carbohydrate polymer with a negative charge that fosters gel-like conditions crucial for its cellular functions and industrial applications. As a recognized ligand for proteins, understanding their mutual interactions provides solid ground to tune hyaluronan's gel properties using biocompatible peptides. This work employs NMR and molecular dynamics simulations to identify molecular motifs relevant to hyaluronan-peptide interactions using arginine, lysine, and glycine oligopeptides. Arginine-rich peptides exhibit the strongest binding to hyaluronan according to chemical shift perturbation measurements, followed distantly by the similarly charged lysine. This difference highlights the significance of electrostatics and the peculiarities of the guanidinium side chain in arginine, capable of non-polar interactions that further stabilize the binding. Additional nuclear Overhauser effect measurements do not show stable interaction partners, precluding strong and well-defined complexes. Finally, molecular simulations support our findings and show an extended but significant interaction region, especially for arginine, responsible for the observed enhanced binding, which can also promote cross-linking of hyaluronan polymers. Our findings pave the way for optimizing biocompatible peptides to alter hyaluronan gels' properties efficiently and also explain why hyaluronan-protein interaction typically involves positively charged arginine-rich regions also capable of forming hydrogen bonds and non-polar interactions.

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 Prague 6 16000 Czech Republic

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$a Riopedre-Fernandez, Miguel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 16000, Czech Republic

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$a Hyaluronan-arginine enhanced and dynamic interaction emerges from distinctive molecular signature due to electrostatics and side-chain specificity / $c M. Riopedre-Fernandez, D. Biriukov, M. Dračínský, H. Martinez-Seara

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$a Hyaluronan is a natural carbohydrate polymer with a negative charge that fosters gel-like conditions crucial for its cellular functions and industrial applications. As a recognized ligand for proteins, understanding their mutual interactions provides solid ground to tune hyaluronan's gel properties using biocompatible peptides. This work employs NMR and molecular dynamics simulations to identify molecular motifs relevant to hyaluronan-peptide interactions using arginine, lysine, and glycine oligopeptides. Arginine-rich peptides exhibit the strongest binding to hyaluronan according to chemical shift perturbation measurements, followed distantly by the similarly charged lysine. This difference highlights the significance of electrostatics and the peculiarities of the guanidinium side chain in arginine, capable of non-polar interactions that further stabilize the binding. Additional nuclear Overhauser effect measurements do not show stable interaction partners, precluding strong and well-defined complexes. Finally, molecular simulations support our findings and show an extended but significant interaction region, especially for arginine, responsible for the observed enhanced binding, which can also promote cross-linking of hyaluronan polymers. Our findings pave the way for optimizing biocompatible peptides to alter hyaluronan gels' properties efficiently and also explain why hyaluronan-protein interaction typically involves positively charged arginine-rich regions also capable of forming hydrogen bonds and non-polar interactions.

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$a Biriukov, Denys $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 16000, Czech Republic

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$a Dračínský, Martin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 16000, Czech Republic

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$a Martinez-Seara, Hector $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 16000, Czech Republic. Electronic address: hseara@gmail.com

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