Metal3D: Accurate prediction of transition metal ion location via deep learning

Metal ions are essential cofactors for many proteins and about half of the structurally characterized proteins contain a metal ion. Metal ions play a crucial role for many applications such as enzyme design or design of protein-protein interactions because they are biologically abundant, tether to the protein using strong interactions, and have favorable catalytic properties e.g. as Lewis acid. In this work, we develop a convolutional neural network based approach to identify metal binding sites in experimental and computationally predicted protein structures. Comparison with other currently available tools shows that Metal3D is the most accurate metal ion location predictor to date using a single structure as input. Metal3D outputs a confidence metric for each predicted site and works on proteins with few homologes in the protein data bank. The predicted metal ion locations for Metal3D are within 0.70 ± 0.64 \AA\, of the experimental locations with half of the sites below 0.5 \AA . Metal3D predicts a global metal density that can be used for annotation of structures predicted using e.g.~AlphaFold2 and a per residue metal density that can be used in protein design workflows for the location of suitable metal binding sites and rotamer sampling to create novel metalloproteins.