BioMetAll: Identifying Metal-Binding Sites in Proteins from Backbone Preorganization.

With a large amount of research dedicated to decoding how metallic species bind to proteins, in silico methods are interesting allies for experimental procedures. To date, computational predictors mostly work by identifying the best possible sequence or structural match of the target protein with metal-binding templates. These approaches are fundamentally focused on the first coordination sphere of the metal. Here, we present the BioMetAll predictor that is based on a different postulate: the formation of a potential metal-binding site is related to the geometric organization of the protein backbone. We first report the set of convenient geometric descriptors of the backbone needed for the algorithm and their parameterization from a statistical analysis. Then, the successful benchmark of BioMetAll on a set of more than 90 metal-binding X-ray structures is presented. Because BioMetAll allows structural predictions regardless of the exact geometry of the side chains, it appears extremely valuable for systems whose structures (either experimental or theoretical) are not optimal for metal-binding sites. We report here its application on three different challenging cases: (i) the modulation of metal-binding sites during conformational transition in human serum albumin, (ii) the identification of possible routes of metal migration in hemocyanins, and (iii) the prediction of mutations to generate convenient metal-binding sites for biocatalysts. This study shows that BioMetAll offers a versatile platform for numerous fields of research at the interface between inorganic chemistry and biology and allows to highlight the role of the preorganization of the protein backbone as a marker for metal binding. BioMetAll is an open-source application available at https://github.com/insilichem/biometall.