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000943415 1001_ $$0P:(DE-Juel1)192214$$aZuo, Ke$$b0$$ufzj
000943415 245__ $$aPredictions of the Poses and Affinity of a Ligand over the Entire Surface of a NEET Protein: The Case of Human MitoNEET
000943415 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2023
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000943415 520__ $$aHuman NEET proteins contain two [2Fe–2S] iron–sulfur clusters, bound to three Cys residues and one His residue. They exist in two redox states. Recently, these proteins have revealed themselves as attractive drug targets for mitochondrial dysfunction-related diseases, such as type 2 diabetes, Wolfram syndrome 2, and cancers. Unfortunately, the lack of information and mechanistic understanding of ligands binding to the whole functional, cytoplasmatic domain has limited rational drug design approaches. Here, we use an enhanced sampling technique, volume-based metadynamics, recently developed by a team involving some of us, to predict the poses and affinity of the 2-benzamido-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-thiophene-3-carboxylate ligand to the entire surface of the cytoplasmatic domain of the human NEET protein mitoNEET (mNT) in an aqueous solution. The calculations, based on the recently published X-ray structure of the complex, are consistent with the measured affinity. The calculated free energy landscape revealed that the ligand can bind in multiple sites and with poses other than the one found in the X-ray. This difference is likely to be caused by crystal packing effects that allow the ligand to interact with multiple adjacent NEET protein copies. Such extra contacts are of course absent in the solution; therefore, the X-ray pose is only transient in our calculations, where the binding free energy correlates with the number of contacts. We further evaluated how the reduction and protonation of the Fe-bound histidine, as well as temperature, can affect ligand binding. Both such modifications introduce the possibility for the ligand to bind in an area of the protein other than the one observed in the X-ray, with no or little impact on affinity. Overall, our study can provide insights on the molecular recognition mechanisms of ligand binding to mNT in different oxidative conditions, possibly helping rational drug design of NEET ligands.
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000943415 7001_ $$0P:(DE-Juel1)174546$$aCapelli, Riccardo$$b1
000943415 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b2
000943415 7001_ $$0P:(DE-HGF)0$$aNechushtai, Rachel$$b3
000943415 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b4$$eCorresponding author
000943415 773__ $$0PERI:(DE-600)1491237-5$$a10.1021/acs.jcim.2c01280$$gVol. 63, no. 2, p. 643 - 654$$n2$$p643 - 654$$tJournal of chemical information and modeling$$v63$$x0095-2338$$y2023
000943415 8564_ $$uhttps://juser.fz-juelich.de/record/943415/files/Invoice_APC600376339.pdf
000943415 8564_ $$uhttps://juser.fz-juelich.de/record/943415/files/Authors%27%20version.docx$$yPublished on 2023-01-09. Available in OpenAccess from 2024-01-09.
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