Unveiling V^IVO²⁺ Binding Modes to Human Serum Albumins by an Integrated Spectroscopic–Computational Approach

Abstract

Human serum albumin (HSA) is involved in the transport of metal ions and potential metallodrugs. Depending on the metal, several sites are available, among which are N‐terminal (NTS) and multi‐metal binding sites (MBS). Despite the large number of X‐ray determinations for albumins, only one structure with Zn2+ is available. In this work, the binding to HSA of the VIVO2+ ion was studied by an integrated approach based on spectroscopic and computational methods, which allowed the systems to be characterized even in the absence of X‐ray analysis. The behavior depends on the type of albumin, defatted (HSAd) or fatted (HSAf). With HSAd ‘primary’ and ‘secondary’ sites were revealed, NTS with (His3, His9, Asp13, Asp255) and MBS with (His67, His247, Asp249, Asn99 or H2O); with increasing the ratio VIVO2+/HSAd, ‘tertiary’ sites, with one His‐N and other donors (Asp/Glu‐O or carbonyl‐O) are populated. With HSAf, fatty acids (FAs) cause a rotation of the subdomains IA and IIA, which results in the formation of a dinuclear ferromagnetic adduct (VIVO)2D(HSAf) with a μ1,1‐Asp249 and the binding of His247, Glu100, Glu252, and His67 or Asn99. FAs hinder also the binding of VIVO2+ to the MBS.

Spectroscopic/Computational Characterization and the X-ray Structure of the Adduct of the VIVO–Picolinato Complex with RNase A

“…The mechanism of action of these compounds is not entirely defined, but a crucial role in the pharmacokinetics of these molecules is played by their interaction with proteins. 5a , 12 , 13 For example, the antidiabetic activity of VCs is based on the inhibition of phosphatases by the H 2 V V O 4 – /V IV O(OH) 3 – anion, 5a , 6f , 14 , 15 and the interaction with human serum transferrin (HTf) 16 , 17 and human serum albumin (HSA) 18 , 19 in the serum and hemoglobin (Hb) 20 , 21 inside the red blood cells plays a key role in the transport of vanadium species in the bloodstream. The involvement of HTf in the cellular uptake of VCs has also been proposed and discussed.…”

Effect of Tetraphenylborate on Physicochemical Properties of Bovine Serum Albumin

“…It is also worth highlighting that albumins are one of the main objects of study in the field of bioinorganic-and metallo-drug design [15][16][17]. However, in the frame of biological studies, cell culture media used in cytotoxicity assays of new compounds usually contain relatively high amount of BSA (ca.…”

Integrated experimental/computational approaches to characterize the systems formed by vanadium with proteins and enzymes

“…130 To unveil the binding of V IV O 2+ with both defatted (HSA d ) and fatted (HSA f ) albumins, we applied an integrated strategy based on EPR spectroscopy, MD, docking and DFT methods. 131 EPR spectra recorded on the binary system V IV O 2+ / HSA d as a function of pH and molar ratio display the signals of (i) a primary and a secondary site with similar A z values compatible with two equatorial His-N plus a number of O donors stemming from carboxylates (Asp and/or Glu), carbonyl or H 2 O; and (ii) tertiary weaker sites involving the coordination of only one His-N and O donors (Fig. 6).…”