Metal-oriented tertiary structural motifs: a minimal set of bricks for metal coordination in proteins

Metal cofactors are often essential for the proper folding of polypeptide chains or function of folded proteins[1]. However, the full potential of protein ligands to bind any given metal cofactors and tune their chemistry has not been exhaustively explored by evolution[2–4]. It has been shown that the protein structural space is highly degenerate and can be recapitulated with a finite set of structural units, such as elements of tertiary structure called TERMs (TERtiary Motifs).[5] Here, we build on this concept and report the development of a dataset of highly specialized metal-binding elements: MetalTERMs. Over 100’000 MetalTERMs were identified from sites in which the metal was bound only by protein residues and water molecules. Subsequently, MetalTERMs were clustered according to their root-mean-square-deviation, the total number of residues and the number of non-contiguous segments. We find that the number of clusters rapidly drops with the increase in complexity of the tertiary arrangement, and that MetalTERMs composed of at most three segments can recapitulate about 90% of the whole dataset. This would indicate that medium to long-range mutations have most likely only a marginal effect on the metal coordination sphere, and would therefore corroborate the well-established adoption of the miniaturization approach for designing metalloproteins from scratch. Our analyses have also enabled us to identify new-to-nature combinations of most recurring MetalTERMs, which could eventually lead to the design of unprecedented catalysts.