Modeling the Detailed Conformational Effects of the Lactosylation of Hyaluronic Acid

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.

透明质酸（Hyaluronic acid, HA）是一类天然且生物相容性优异的多糖，可与CD44受体相互作用，调控炎症反应、纤维化进程与组织重建。其可作为适配的化学载体用于药物递送，还可通过药效基团与/或可导向基团进行功能化修饰。通过1-氨基-1-脱氧乳糖醇与透明质酸的羧基发生酰胺化反应，可实现不同程度的透明质酸衍生化，得到接枝聚合物HYLACH。尽管与多数透明质酸接枝聚合物类似，此类取代反应带来的具体构象效应虽在药物递送系统的设计与优化中至关重要且尚未明确，但该衍生物仍保留了透明质酸的广谱特性。本研究通过多组独立分子动力学模拟，对乳糖基化透明质酸衍生物的构象、粒径、二级结构、氢键网络及水化特征进行了表征分析。结果显示，该透明质酸载体虽仅存在细微变化，但仍存在显著的特性改变，且接枝密度是决定其性能的核心参数。