Human NEET proteins, such as NAF-1 and mitoNEET, are homodimeric, redox iron-sulfur proteins characterized by triple cysteine and one histidine-coordinated [2Fe-2S] cluster. They exist in an oxidized and reduced state. Abnormal release of the cluster is implicated in a variety of diseases, including cancer and neurodegeneration. The computer-aided and structure-based design of ligands affecting cluster release is of paramount importance from a pharmaceutical perspective. Unfortunately, experimental structural information so far is limited to only one ligand/protein complex. This is the X-ray structure of furosemide bound to oxidized mitoNEET. Here we employ an enhanced sampling approach, Localized Volume-based Metadynamics, developed by some of us, to identify binding poses of furosemide to human mitoNEET protein in solution. The binding modes show a high variability within the same shallow binding pocket on the protein surface identified in the X-ray structure. Among the different binding conformations, one of them is in agreement with the crystal structure’s one. This conformation might have been overstabilized in the latter because of the presence of crystal packing interactions, absent in solution. The calculated binding affinity is compatible with experimental data. Our protocol can be used in a straightforward manner in drug design campaigns targeting this pharmaceutically important family of proteins.

Multiple Poses and Thermodynamics of Ligands Targeting Protein Surfaces: The Case of Furosemide Binding to mitoNEET in Aqueous Solution / L.G. Hoang, J. Gossen, R. Capelli, T.T. Nguyen, Z. Sun, K. Zuo, J.B. Schulz, G. Rossetti, P. Carloni. - In: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY. - ISSN 2296-634X. - 10:(2022), pp. 886568.1-886568.8. [10.3389/fcell.2022.886568]

Multiple Poses and Thermodynamics of Ligands Targeting Protein Surfaces: The Case of Furosemide Binding to mitoNEET in Aqueous Solution

R. Capelli
;
2022

Abstract

Human NEET proteins, such as NAF-1 and mitoNEET, are homodimeric, redox iron-sulfur proteins characterized by triple cysteine and one histidine-coordinated [2Fe-2S] cluster. They exist in an oxidized and reduced state. Abnormal release of the cluster is implicated in a variety of diseases, including cancer and neurodegeneration. The computer-aided and structure-based design of ligands affecting cluster release is of paramount importance from a pharmaceutical perspective. Unfortunately, experimental structural information so far is limited to only one ligand/protein complex. This is the X-ray structure of furosemide bound to oxidized mitoNEET. Here we employ an enhanced sampling approach, Localized Volume-based Metadynamics, developed by some of us, to identify binding poses of furosemide to human mitoNEET protein in solution. The binding modes show a high variability within the same shallow binding pocket on the protein surface identified in the X-ray structure. Among the different binding conformations, one of them is in agreement with the crystal structure’s one. This conformation might have been overstabilized in the latter because of the presence of crystal packing interactions, absent in solution. The calculated binding affinity is compatible with experimental data. Our protocol can be used in a straightforward manner in drug design campaigns targeting this pharmaceutically important family of proteins.
furosemide; furosemide binding pose and affinity; localized volume-based metadynamics; molecular dynamics; NEET proteins; rational drug design; [2Fe-2S] cluster
Settore BIO/10 - Biochimica
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore CHIM/02 - Chimica Fisica
H20_RIA20MMASS_01 - Human Brain Project Specific Grant Agreement 3 (HBP SGA3) - MASSIMINI, MARCELLO - H20_RIA - Horizon 2020_Research & Innovation Action/Innovation Action - 2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/933808
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