Journal Article

FZJ-2022-02005

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multiple Poses and Thermodynamics of Ligands Targeting Protein Surfaces: The Case of Furosemide Binding to mitoNEET in Aqueous Solution

Hoang Gia, L.FZJ* ; Goßen, J. ; Capelli, R. (Corresponding author) ; Nguyen, T. T. ; Sun, Z. ; Zuo, K.FZJ* ; Schulz, J. B.FZJ* ; Rossetti, G. (Corresponding author)FZJ* ; Carloni, P.FZJ*

2022
Frontiers Media Lausanne

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Please use a persistent id in citations: http://hdl.handle.net/2128/31081  doi:10.3389/fcell.2022.886568

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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. Jülich Supercomputing Center (JSC)

Research Program(s):

1. 5252 - Brain Dysfunction and Plasticity (POF4-525) (POF4-525)
2. 5251 - Multilevel Brain Organization and Variability (POF4-525) (POF4-525)
3. 5111 - Domain-Specific Simulation Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
4. DFG project 291198853 - FOR 2518: Funktionale Dynamik von Ionenkanälen und Transportern - DynIon - (291198853)

Appears in the scientific report 2022

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Database coverage:
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