Unveiling VIV O2+ Binding Modes to Human Serum Albumins by an Integrated Spectroscopic-Computational Approach.

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 VIV O2+ 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 H2 O); with increasing the ratio VIV O2+ /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 (VIV O)2 D (HSAf ) with a μ1,1 -Asp249 and the binding of His247, Glu100, Glu252, and His67 or Asn99. FAs hinder also the binding of VIV O2+ to the MBS.