Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamilnadu, 600 006, India.
J Comput Aided Mol Des. 2018 Aug;32(8):821-840. doi: 10.1007/s10822-018-0131-0. Epub 2018 Jul 6.
Heparanase (HPSE) is an endo-β-D-glucuronidase that has diverse functions in mammals which includes cell survival, cell adhesion and cell migration. HPSE features both enzymatic and non-enzymatic functionalities in a pH dependent manner. Hence, in this study, an extensive molecular dynamics simulation, molecular docking, protein Angular dispersion analysis were performed for apo form and holo forms to understand its conformational changes at varied pH conditions. On comparative conformational analysis of apo and holo forms, it was inferred that the HSPE has undergone pH dependent structural changes, thereby affecting the binding of Heparan sulfate proteoglycan (HSPG). Moreover, HPSE also showed favourable structural changes for optimal binding of HSPG at pH 5.0 and 6.0, as inferred from functional flap displacements within HPSE. Thus, this study provides significant insights on optimal pH for HPSE to exhibit its enzymatic activity. The outcome of this study shall aid in ideal lead generation for targeting HPSE mediated disease conditions.
肝素酶 (HPSE) 是一种内-β-D-葡糖醛酸酶，在哺乳动物中有多种功能，包括细胞存活、细胞黏附和细胞迁移。HPSE 以依赖 pH 的方式具有酶和非酶功能。因此，在这项研究中，我们对 apo 形式和 holo 形式进行了广泛的分子动力学模拟、分子对接和蛋白质角散布分析，以了解其在不同 pH 条件下的构象变化。通过对 apo 和 holo 形式的构象比较分析，推断出 HPSE 发生了依赖 pH 的结构变化，从而影响了肝素硫酸蛋白聚糖 (HSPG) 的结合。此外，HPSE 还显示出有利于在 pH 5.0 和 6.0 下与 HSPG 最佳结合的结构变化，这是从 HPSE 内功能瓣位移推断出来的。因此，这项研究为 HPSE 发挥其酶活性的最佳 pH 值提供了重要的见解。这项研究的结果将有助于针对 HPSE 介导的疾病条件生成理想的先导化合物。
