Structural Bioinformatics and Deep Learning of Metalloproteins: Recent Advances and Applications

Abstract

All living organisms require metal ions for their energy production and metabolic and biosynthetic processes. Within cells, the metal ions involved in the formation of adducts interact with metabolites and macromolecules (proteins and nucleic acids). The proteins that require binding to one or more metal ions in order to be able to carry out their physiological function are called metalloproteins. About one third of all protein structures in the Protein Data Bank involve metalloproteins. Over the past few years there has been tremendous progress in the number of computational tools and techniques making use of 3D structural information to support the investigation of metalloproteins. This trend has been boosted by the successful applications of neural networks and machine/deep learning approaches in molecular and structural biology at large. In this review, we discuss recent advances in the development and availability of resources dealing with metalloproteins from a structure-based perspective. We start by addressing tools for the prediction of metal-binding sites (MBSs) using structural information on apo-proteins. Then, we provide an overview of the methods for and lessons learned from the structural comparison of MBSs in a fold-independent manner. We then move to describing databases of metalloprotein/MBS structures. Finally, we summarizing recent ML/DL applications enhancing the functional interpretation of metalloprotein structures.

MetalProGNet: a structure-based deep graph model for metalloprotein–ligand interaction predictions

“…Aer this, for each metalloprotein, we retrieved the ChEMBL database to identify its active ligands. The following rules were utilized to lter the raw records: (1) the active ligands should be labeled with clear activity data (K i , K d or IC 50 ); (2) the molecular weight of the active ligands should be in the range from 200 to 800; (3) to guarantee the diversity of the active ligands, the total number of the identied active ligands for a protein should be greater than 100. Eventually, the independent test dataset contains about 25 000 active ligands toward 22 metalloproteins.…”

“…As for the catalytic role, some metal ions located in the active sites of enzymes can facilitate catalysis. Additionally, it has been reported that at least 40% of enzymes require metal ions for their bioactivities, 3 and such enzymes can be categorized as metalloenzymes. [4][5][6] The extensive effects of metal ions have made metalloproteins widely involved in a wide variety of biological processes (such as enzymatic catalysis and signal transcription) and pathologies (such as cancer and inammation).…”

Unlocking Precision Docking for Metalloproteins

“…13 Moreover, it is estimated that at least 40% of all enzymes need metal ions for their bioactivities. 14 Despite their relevance and potential as targets, the search for highaffinity ligands targeting metalloproteins has been delayed. 15 Concerning, docking programs, only a few of them, such as GPDOCK, 16 FlexX, 17 AutoDockZn, 18 MpsDockZn, 19 and GM-DockZn, 20 are specially developed for metalloproteins, and most of them are predominantly specific for zinc metalloproteins.…”

“…Metalloproteins, which refer to proteins with at least one metal ion in their structure, comprise close to half of the human proteome and perform structural, regulatory, and catalytic functions . Moreover, it is estimated that at least 40% of all enzymes need metal ions for their bioactivities . Despite their relevance and potential as targets, the search for high-affinity ligands targeting metalloproteins has been delayed .…”

A database overview of metal-coordination distances in metalloproteins

“…Numerous databases exist that address MPs either in general or some specific aspects of their chemistry and biology (Zhang & Zheng, 2020;Andreini & Rosato, 2022). Of particular relevance for this work are MetalPDB (Andreini et al, 2013;Putignano et al, 2018) and MESPEUS (Lin et al, 2024;Hsin et al, 2008), both of which address the structural and functional properties of all metal-binding sites present in the PDB.…”