CD44 is a single-pass transmembrane glycoprotein implicated in diseases such as inflammation and cancer. Its interactions with the extracellular glycosaminoglycan hyaluronan (HA) mediate cell adhesion and migration, contributing to cancer invasiveness and metastasis. Several isoforms of CD44 exist due to alternative splicing and various post-translational modifications, including glycosylation, resulting in substantial structural diversity. These variations appear to be dependent on cell-line and state. The conserved portion of the HA binding domain (HABD) contains 5 possible N-glycosylation sites. It has been shown that N-glycans with terminal sialic acids have an inhibitory effect on HA binding, though it is unclear how this occurs. Molecular dynamics (MD) simulations can give insight to the atomic-level interactions responsible for macroscopic changes in CD44-HA binding affinity. For the human CD44 HA binding domain, there are currently no publicly-known atomic resolution structures in the glycosylated form, though unglycosylated forms are available. In-silico glycosylation of CD44 HABD with sialic acid-terminal N-glycans and their asialo- versions was used to generate a series of 6 glycoforms each for two different atomic-resolution structures for MD simulations. From the simulations, the covalently bound glycans are highly dynamic and interact with protein residues. Notably, terminal sialic acid moieties interact with basic amino acids of the protein.

Molecular dynamics investigation of CD44 hyaluronan binding domain with sialic acid-terminal N-glycans

245th National Meeting (2013)

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