Magnesium and manganese binding sites on proteins have the same predominant motif of secondary structure

•BCH and BCB motifs are predominant for both Mg2+ and Mn2+ binders.•“Asp-Xaa-His” motif is used for Mn2+ binding but avoided by Mg2+ ions.•Number of amino acid residues necessary for Mg2+ ions binding is lower than for Mn2+.•Usually already bound Mg2+ and Mn2+ ions attract phosphates to BCH and BCB regions.•Some BCH and BCB regions can coordinate Mn2+ with the help of phosphates only.

Manganese ion (Mn2+) can substitute magnesium ion (Mg2+) in active sites of numerous enzymes. Binding sites for these two ions have been studied in two sets of protein 3D structures from the Protein Data Bank with the homology level lower than 25%. The structural motif “beta strand – binder – random coil” is predominant in both Mn2+ and Mg2+ coordination spheres, especially in functionally relevant ones. That predominant motif works as an active binder of those divalent cations which can then attract additional ligands, such as different phosphate-containing compounds. In contrast, such Mg2+ and Mn2+ binding motif as “GK(T/S)T” being the N-terminal part of alpha helices works as an active binder of phosphates which can then attract divalent cations. There are few differences between Mg2+ and Mn2+ coordination spheres responsible of the cation specificity. His residues are underrepresented in certain positions around Asp and Glu residues involved in Mg2+ coordination, while they are overrepresented in certain positions around Asp and Glu residues coordinating Mn2+. The random coil region in the “beta strand – random coil – alpha helix” motif for Mg2+ binding is usually shorter than that in the same motif for Mn2+ coordination. This feature is associated with the lower number of binding amino acids (and lower levels of usage of such “major” binders as Asp and Glu) for Mg2+ (which is a hard Lewis acid) in comparison with those for Mn2+ (an intermediate Lewis acid).