Abstract：
The endohedral metallofullerenol Gd@C82(OH)22 has been identified as a possible antineoplastic agent that can inhibit both the growth and metastasis of cancer cells. Despite these potentially important effects, our understanding of the interactions between Gd@C82(OH)22 and biomacromolecules remains incomplete. Here, we study the interaction between Gd@C82(OH)22 and the human voltage-dependent anion channel 1 (hVDAC1), the most abundant porin embedded in the mitochondrial outer membrane (MOM), and a potential druggable target for novel anticancer therapeutics. Using in silico approaches, we observe that Gd@C82(OH)22 molecules can permeate and form stable interactions with the pore of hVDAC1. Further, this penetration can occur from either side of the MOM to elicit blockage of the pore. The binding between Gd@C82(OH)22 and hVDAC1 is largely driven by long-range electrostatic interactions. Analysis of the binding free energies indicates that it is thermodynamically more favorable for Gd@C82(OH)22 to bind to the hVDAC1 pore when it enters the channel from inside the membrane rather than from the cytoplasmic side of the protein. Multiple factors contribute to the preferential penetration, including the surface electrostatic landscape of hVDAC1 and the unique physicochemical properties of Gd@C82(OH)22. Our findings provide insights into the potential molecular interactions of macromolecular biological systems with the Gd@C82(OH)22 nanodrug.
摘要：
金属富勒烯内Gd@C82（OH）22已被确定为可能的抗肿瘤剂，可以抑制癌细胞的生长和转移。尽管有这些潜在的重要影响，我们对Gd@C82（OH）22与生物大分子之间的相互作用的理解仍然不完整。这里,我们研究了Gd@C82（OH）22与人电压依赖性阴离子通道1（hVDAC1）之间的相互作用，嵌入线粒体外膜（MOM）中的最丰富的孔蛋白，和新型抗癌疗法的潜在药物靶标。使用计算机模拟方法，我们观察到Gd@C82（OH）22分子可以渗透并与hVDAC1的孔形成稳定的相互作用。Further,这种渗透可以从MOM的任一侧发生以引起孔的堵塞。Gd@C82(OH)22与hVDAC1之间的结合主要由长程静电相互作用驱动。结合自由能的分析表明，当Gd@C82（OH）22从膜内部而不是从蛋白质的细胞质侧进入通道时，它在热力学上更有利于结合hVDAC1孔。多种因素促成优惠渗透，包括hVDAC1的表面静电景观和Gd@C82(OH)22的独特物理化学性质。我们的发现为大分子生物系统与Gd@C82（OH）22纳米药物的潜在分子相互作用提供了见解。
