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.
Highlights
Gadolinium endohedral fullerenol Gd@C82 (OH)22 is a nanomaterial that was initially designed as a contrast agent for magnetic resonance imaging (MRI) [1,2]
We focus on the interaction between Gd@C82 (OH)22 and the voltage-dependent anion channel (VDAC), the most abundant channel protein embedded in the mitochondrial outer membrane (MOM) [28,29]
molecular dynamics (MD) simulation was conducted to test the structural stability of human voltage-dependent anion channel 1 (hVDAC1) in the membrane
Summary
Gadolinium endohedral fullerenol Gd@C82 (OH) is a nanomaterial that was initially designed as a contrast agent for magnetic resonance imaging (MRI) [1,2]. Adopting an in silico approach, our group identified the binding interface for Gd@C82 (OH) on MMP-9, revealing the molecular mechanism by which Gd@C82 (OH) inhibits enzyme activity This insight provided a framework for studying how MMP-9 inhibition can lead to the imprisonment of cancer cells by (i) reducing tumor angiogenesis, (ii) preserving the extracellular matrix, and (iii) reducing subsequent metastasis [12]. Blockage from the inside of the MOM (abbreviated as inside of membrane, IM) is energetically preferable to that from the outside of the MOM (abbreviated as outside of membrane, OM); further, both blocked-binding modes are energetically more favorable than the unblocked binding modes observed in the MD simulations These results imply that Gd@C82 (OH) may perturb the activity of the mitochondrial porin protein hVDAC1 and interfere with the biological functions of the mitochondria.
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