Charging nanoparticles: increased binding of Gd@C82(OH)22 derivatives to human MMP-9
Charging nanoparticles: increased binding of Gd@C82(OH)22 derivatives to human MMP-9
复制标题
带电纳米粒子：增加 Gd@C-82(OH)(22) 衍生物与人 MMP-9 的结合
DOI：
10.1039/c8nr00127h
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发表时间：
2018-03-28
期刊：
影响因子：
6.7
通讯作者：
Zhou, Ruhong
中科院分区：
文献类型：
--
作者：
Chen, Serena H.;Kang, Seung-gu;Zhou, Ruhong
与靶向保守的催化锌位点的大多数基质金属蛋白酶（MMP）抑制剂不同，Gd@C-82（OH）（22）通过结合配体特异性S1'环间接抑制MMP-9活性。变构结合使得Gd@C-82（OH）（22）成为MMP-9的有希望的选择性抑制剂。然而，芳族碳笼的疏水性质可能导致Gd@C-82（OH）（22）在水溶液中自聚集，从而削弱结合。在这项研究中，我们设计了Gd@C-82（OH）（22）衍生物，旨在提高MMP-9的结合亲和力。在富勒烯醇表面上的羟基被新的官能团（-PO 42-、-CH 2CO 2-、-CO 2-、-NH 3（+）或-CONH 2）取代的突变后，我们使用自由能微扰（FEP）方法计算了与人MMP-9的催化结构域的结合自由能的变化。我们发现，官能团的净电荷越高，结合越强。与Gd@C-82（OH）（22）相比，Gd@C-82（OH）（21）（PO 4）（2-）与MMP-9的结合至少强1.5至2.5 kcal mol（-1）。结合是由磷酸基团和结合位点处的带电残基之间的静电相互作用特异性控制的。除了净电荷之外，结合自由能还可以通过其他因素进行精细调节，例如Gd@C-82（OH）（22）上的官能化位点、MMP-9的推定结合位点的局部环境以及带电官能团附近离子的存在。我们的研究结果揭示了开发Gd@C-82（OH）（22）衍生物作为纳米药物用于治疗与不受调节的MMP-9活性相关的病理性疾病的潜力。
Unlike most matrix metalloproteinase (MMP) inhibitors, which target the conserved catalytic zinc site, Gd@C-82(OH)(22) indirectly inhibits MMP-9 activity by binding at the ligand specificity S1' loop. The allosteric binding makes Gd@C-82(OH)(22) a promising inhibitor selective for MMP-9. However, the hydrophobic nature of the aromatic carbon cage may cause Gd@C-82(OH)(22) to self-aggregate in aqueous solutions, hence weakening the binding. In this study, we designed Gd@C-82(OH)(22) derivatives aiming at improving the binding affinity for MMP-9. Upon a mutation that substitutes a new functional group (-PO42-, -CH2CO2-, -CO2-, -NH3(+), or -CONH2) for a hydroxyl group on the fullerenol surface, we calculated the changes in the binding free energy to the catalytic domain of human MMP-9 using the free energy perturbation (FEP) method. We found that the higher the net charge of the functional group, the stronger the binding. Compared with Gd@C-82(OH)(22), Gd@C-82(OH)(21)(PO4)(2-) binds at least 1.5 to 2.5 kcal mol(-1) more strongly to MMP-9. The binding is specifically controlled by electrostatic interactions between the phosphate group and the charged residues at the binding site. In addition to the net charge, the binding free energy can be delicately adjusted by other factors, such as the functionalization site on Gd@C-82(OH)(22), the local environment of the putative binding site of MMP-9, and the presence of ions near the charged functional group. The results of our study shed light on the potential of developing Gd@C-82(OH)(22) derivatives as nanodrugs for treating the pathological diseases associated with unregulated MMP-9 activity.