Hyaluronic acid (HA) is a natural and biocompatible polysaccharide that is able to interact with CD44 receptors to regulate inflammation, fibrosis, and tissue reconstruction. It is a suitable chemical scaffold for drug delivery that can be functionalized with pharmacophores and/or vectorizable groups. The derivatization of HA is achieved to varying extents by reacting 1-amino-1-deoxy-lactitol via the carboxyl group to form amide linkages, giving rise to the grafted polymer, HYLACH. This retains the broad properties of HA, even though, 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 conformation, size, secondary structure, hydrogen bond network, and hydration features of lactosylated HA derivatives were evaluated by using multiple independent molecular dynamics simulations. This revealed subtle but nevertheless significant changes in the HA scaffold, establishing the density of grafting as the key parameter determining its properties.