Modelling the Detailed Conformational Effects of the Lactosylation of Hyaluronic Acid

Hyaluronic acid (HA) is a natural and biocompatible polysaccharide which is able to interact with CD44 receptors to regulate inflammation, fibrosis and tissue reconstruction. It is also a suitable chemical scaffold for drug-delivery to be functionalized with pharmacophore and/or vectorizable groups. The derivatisation of HA can be achieved to varying extents by reacting 1-amino-1-deoxy-lactitol, via the carboxyl group to form amide linkages, giving rise to a grafted polymer named HYLACH®. This retains the broad properties of HA, while coupling its intrinsic properties to those of the substituents, with the crucial advantage that it is more resistant to enzymatic degradation. As in most HA grafted polymers, the detailed conformational effects of such substitutions, while crucial in the design or optimization of drug-delivery systems, remain unknown. Here, the conformational, size, secondary structure, and hydrogen bond network of lactosylated HA derivatives are evaluated employing multiple independent molecular dynamics simulations, that reveal subtle, but nevertheless, significant changes in the HA scaffold, underlining the primary role of the density of grafting in affecting these properties. This study establishes that the density of grafting remains a key structural variable when designing grafted HA polymers for advanced applications such as drug-delivery or drug-vectorization.