Molecular mechanism of binding selectivity in four stereoisomeric europium complexes with human serum albumin

A series of stereoisomeric europium complexes displays stereoselectivity in binding to the major human transport protein human serum albumin, (HSA). Details of the nature of the binding interaction between two pairs of chiral Eu(iii) complexes and drug site 2 in HSA have been investigated using molecular modelling calculations. Ensemble docking and refinement were carried out in all-atom molecular dynamics simulations, allowing an assessment of the salient binding poses. This approach allowed a comparison with experimental data and was able to rationalise relative binding free energies, and trace the origins of the differences in binding affinity, in terms of selective van de Waals’, hydrogen bonding and cation–π interactions to proximate amino-acid residues, notably Arg-410 and Lys-414, in drug site 2. Details were revealed of how the binding of each complex to HSA affects the conformational preference of the protein and the Eu(iii) complex, providing insight into the origins of the observed selectivity.