A Comprehensive Computational Study of the Interaction between Human Serum Albumin and Fullerenes

Abstract

Human serum albumin (HSA) is the most abundant blood plasma protein, which transports fatty acids, hormones, and drugs. We consider nanoparticle-HSA interactions by investigating the binding of HSA with three fullerene analogs. Long MD simulations, quantum mechanical (fragment molecular orbital, energy decomposition analysis, atoms-in-molecules), and free energy methods elucidated the binding mechanism in these complexes. Such a systematic study is valuable due to the lack of comprehensive theoretical approaches to date. The main elements of the mechanism include the following: binding to IIA site results in allosteric modulation of the IIIA and heme binding sites with an increase in α-helical structure of IIIA. Fullerenes displayed high binding affinities for HSA; therefore, HSA can be used as a fullerene carrier, facilitating any toxic function the fullerene may exert. Complex formation is driven by hydrogen bonding, van der Waals, nonpolar, charge transfer, and dispersion energy contributions. Proper functionalization of C60 has enhanced its binding to HSA by more than an order of magnitude. This feature may be important for biological applications (e.g., photodynamic therapy of cancer). Satisfactory agreement with relevant experimental and theoretical data has been obtained.

Triplet Fullerenes as Prospective Spin Labels for Nanoscale Distance Measurements by Pulsed Dipolar EPR Spectroscopy

“…Fullerenes show a great potential in numerous biological and medicinal applications and their binding with proteins enhances solubility in water and might facilitate transport to the target sites . The C 60 :HSA complex encompasses 2–4 binding sites within the hydrophobic pockets on the protein surface, but only one of them was identified experimentally up to date, motivating us to probe these sites using the fullerene labels. NIT spin labels were selectively introduced at Cys34 of HSA, and a supramolecular 1:0.25 complex HSA–NIT:PCBM was obtained (Supporting Information), where PCBM is phenyl‐C 61 ‐butyric acid methyl ester (Scheme ).…”

“…The obtained distance distribution shows two different peaks indicating that there are at least two different binding sites for PCBM in HSA (Figure ). Based on the literature, we calculated the anticipated distances between potential C 60 binding sites and the NIT‐labeled Cys34 residue. A major peak at ⟨ r ⟩≈2.6±0.5 nm implies binding of PCBM with the site in the IIA domain, including the region near Trp214 (Supporting Information).…”

“…A major peak at ⟨ r ⟩≈2.6±0.5 nm implies binding of PCBM with the site in the IIA domain, including the region near Trp214 (Supporting Information). This site is favorable for binding with structurally different C 60 derivatives . A smaller peak at 4.3±0.3 nm agrees well with the distances to less favorable binding sites in the IIIA domain of HSA being approximately 4–4.5 nm away (Supporting Information, Figure S13).…”

Triplet Fullerenes as Prospective Spin Labels for Nanoscale Distance Measurements by Pulsed Dipolar EPR Spectroscopy

“…Fullerenes show a great potential in numerous biological and medicinal applications and their binding with proteins enhances solubility in water and might facilitate transport to the target sites . The C 60 :HSA complex encompasses 2–4 binding sites within the hydrophobic pockets on the protein surface, but only one of them was identified experimentally up to date, motivating us to probe these sites using the fullerene labels. NIT spin labels were selectively introduced at Cys34 of HSA, and a supramolecular 1:0.25 complex HSA–NIT:PCBM was obtained (Supporting Information), where PCBM is phenyl‐C 61 ‐butyric acid methyl ester (Scheme ).…”

Weakening Impact of Excessive Human Serum Albumin (eHSA) on Cisplatin and Etoposide Anticancer Effect in C57BL/6 Mice with Tumor and in Human NSCLC A549 Cells

“…It is the most abundant protein in plasma and one of the major binders/carriers of drugs that plays an important role in pharmacokinetic fate (absorption, distribution, metabolism, and excretion) and pharmacodynamics (Kratz and Beyer, 1998; Leonis et al, 2015; Alam et al, 2016; Ma et al, 2016; Zaloga et al, 2016). Since the half-life of HSA is about 15–21 days, it cannot be immediately utilized by the human body, which means that exogenous HSA cannot correct hypoproteinemia immediately in cancer patients (Sikuler et al, 2000; Talasaz et al, 2012).…”