Computing Metal-Binding Proteins for Therapeutic Benefit |
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Authors: | Dr Angelo Spinello Dr Jure Bori?ek Dr Matic Pavlin Dr Pavel Jano? Dr Alessandra Magistrato |
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Affiliation: | 1. National Research Council of Italy (CNR)-, Institute of Materials (IOM) c/o International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy;2. National Institute of Chemistry Institution Hajdrihova ulica 19, 1000 Ljubljana, Slovenia;3. Laboratory of Microsensor Structures and Electronics Faculty of Electrical Engineering, University of Ljubljana Tr?a?ka cesta 25, 1000 Ljubljana, Slovenia |
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Abstract: | Over one third of biomolecules rely on metal ions to exert their cellular functions. Metal ions can play a structural role by stabilizing the structure of biomolecules, a functional role by promoting a wide variety of biochemical reactions, and a regulatory role by acting as messengers upon binding to proteins regulating cellular metal-homeostasis. These diverse roles in biology ascribe critical implications to metal-binding proteins in the onset of many diseases. Hence, it is of utmost importance to exhaustively unlock the different mechanistic facets of metal-binding proteins and to harness this knowledge to rationally devise novel therapeutic strategies to prevent or cure pathological states associated with metal-dependent cellular dysfunctions. In this compendium, we illustrate how the use of a computational arsenal based on docking, classical, and quantum-classical molecular dynamics simulations can contribute to extricate the minutiae of the catalytic, transport, and inhibition mechanisms of metal-binding proteins at the atomic level. This knowledge represents a fertile ground and an essential prerequisite for selectively targeting metal-binding proteins with small-molecule inhibitors aiming to (i) abrogate deregulated metal-dependent (mis)functions or (ii) leverage metal-dyshomeostasis to selectively trigger harmful cells death. |
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Keywords: | Metalloenzymes Metal transporters Molecular Dynamics QM/MM Docking |
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