Abstract
The collagen-integrin interactions are mediated by the doubly charged Mg2+ cation. In nature this cation seems to have the optimal binding strength to stabilize this complex. It is essential that the binding is not too weak so that the complex becomes unstable, however, it is also of importance that the ligand-receptor binding is still labile enough so that the ligand can separate from the receptor in a suited environment. In the case of crystal growing for experimentally useful integrin-collagen fragment complexes it turned out that Co2+ cations are ideal mediators to form stable complexes for such experiments. Although, one can argue that Co2+ is in this context an artificial cation, however, it is now of special interest to test the impact of this cation in cell-culture experiments focusing on integrin-ligand interactions. In order to examine, in particular, the role cobalt ions we have studied a Co2+ based model system using quantum chemical calculations. Thereby, we have shown that hybrid and long-range corrected functional, which are approximations provide already a sufficient level of accuracy. It is of interest to study a potential impact of cations on the binding of collagen-fragments including collagens from various species because different integrins have numerous biological functions (e.g. Integrin – NCAM (Neural cell adhesion molecule) interactions) and are triggered by intact and degraded collagen fragments. Since integrin–carbohydrate interactions play a key role when bio-medical problems such as tumor cell adhesion and virus-host cell infections have to be addressed on a sub-molecular level it is essential to understand the interactions with heavy-metal ions also at the sub-atomic level. Our findings open new routes, especially, in the fields of tissue repair and neuro-oncology for example for cell-culture experiments with different ions. Since Co2+ ions seem to bind stronger to integrin than Mg2+ ions it should be feasible to exchange these cations in suited tumor tissues although different cations are present in other metalloproteins which are active in such tissues. Various staining methods can be applied to document the interactions of integrins with carbohydrate chains and other target structures. Thereby, it is possible to study a potential impact of these interactions on biological functions. It was therefore necessary to figure out first which histological–glycobiological experimental settings of tumor cells are suited for our purpose. Since the interactions of several metalloproteins (integrin, ADAM12) with polysialic acid and the HNK-1 epitope play a crucial role in tumor tissues selected staining methods are proper tools to obtain essential information about the impact of the metal ions under study.
Highlights
In this study we show how to correlate experimental results obtained from Surface Plasmon Resonance (SPR), NMR and X-ray crystallographic analysis with quantum chemical DFT data regarding the transition metal compounds involved
Obtained results on the impact of different ions on the stability of collagen-fragmentintegrin complexes have been derived by Surface Plasmon Resonance (SPR) experiments by some of us (Siebert et al, 2010)
The amount of geometric distortion of the metal complex can be typically assigned to the structural strain that is imposed on the central cation by the respective ligand sphere, i.e. in the vicinity of a rather rigid peptide chain backbone the hexacoordinate Co2+ tends to depart from the assumed Jahn-Teller distortion where a clear distinction of axial and equatorial ligands is abandoned in favor of the overall complexation (cf. e.g. PDB codes 2GRU (Nango et al, 2008) and (Dowling et al, 2010). This is in sharp contrast to whenever geometric flexibility is increased, e.g. via the incorporation of water molecules as ligands at the complex center, in these cases the skeletal strain is relieved considerably allowing for more appropriate structural parameters for the metal complexation spheres (Chen et al, 2018)
Summary
A detailed understanding of integrin–ligand interactions requires that the impact of ligand structures is considered (Racine-Samson et al, 1997; Gabius et al, 2004; Petridis et al, 2011; Glinskii et al, 2014; Hussein et al, 2015; Cornelissen and Van Vliet, 2016; Marsico et al, 2018; Sharma et al, 2020; Eckert et al, 2021). The corresponding data are necessary to understand cellular mechanisms in neuroblastoma and in glioblastoma cells (Hemler, 1990; André et al, 2005; Bhunia et al, 2010; Petridis et al, 2011; Stötzel et al, 2012; Tsvetkov et al, 2012; Kanakis et al, 2013; Zhang et al, 2016a; Malric et al, 2017; Martinez-Olivera et al, 2018; McCarthy et al, 2018; Van Agthoven et al, 2019) This is possible on a sub-molecular size-level, as well as outlined in this article on a sub-atomic scale where orbitalstructures play an essential role. R. esculentum is a very suitable and promising material for cartilage tissue engineering (Hoyer et al, 2014)
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