Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.

中文翻译：

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透明质酸衍生物调节 PDGF/PDGFR-β 复合的结构见解

血管生成是一个重要的生理过程，在伤口愈合和癌症进展中起着至关重要的作用。血管内皮生长因子 (VEGF) 和血小板衍生生长因子 (PDGF) 是血管生成的关键参与者。基于先前关于糖胺聚糖 (GAG) 调节 VEGF 活性的发现，在这里我们通过应用分子建模和动力学模拟结合表面等离子共振来探索基于透明质酸 (HA) 的 GAG 与 PDGF 及其受体 PDGFR-β 的相互作用（SPR）。对具有不同硫酸化模式和功能化的寡透明质酸衍生物相互作用的计算分析表明，这些 GAG 在受体识别的相关区域与 PDGF 相互作用，并且高硫酸化以及与 TAMRA 基团的修饰具有更强的结合力。另一方面，预测研究的寡透明质酸衍生物几乎不识别PDGFR-β。SPR 结果与关于 HA 四糖 (HA4) 衍生物与 PDGF 和 PDGFR-β 的结合模式的计算预测一致。此外，我们的实验结果还表明，PDGF 与 PDGFR-β 的络合可以通过 HA4 衍生物进行调节。结果发现为考虑将 HA4 衍生物作为潜在候选物开辟了道路，可用于在血管生成和相关疾病状况中调节 PDGF/PDGFR-β 信号系统。我们的实验结果还表明，PDGF 与 PDGFR-β 的络合可以通过 HA4 衍生物进行调节。结果发现为考虑将 HA4 衍生物作为潜在候选物开辟了道路，可用于在血管生成和相关疾病状况中调节 PDGF/PDGFR-β 信号系统。我们的实验结果还表明，PDGF 与 PDGFR-β 的络合可以通过 HA4 衍生物进行调节。结果发现为考虑将 HA4 衍生物作为潜在候选物开辟了道路，可用于在血管生成和相关疾病状况中调节 PDGF/PDGFR-β 信号系统。