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Article

The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

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VNU Key Laboratory for Multiscale Simulation of Complex Systems, VNU University of Science, Vietnam National University, Hanoi 11416, Vietnam
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Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, D-52425 Jülich, Germany
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Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, D-52425 Jülich, Germany
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Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy
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Jülich Supercomputing Center (JSC), Forschungszentrum Jülich, 52428 Jülich, Germany
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University Hospital Aachen, RWTH Aachen University, 52078 Aachen, Germany
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Department of Physics, RWTH Aachen University, 52078 Aachen, Germany
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JARA-BRAIN Institute “Molecular Neuroscience and Neuroimaging” INM-11, Forschungszentrum Jülich, 52428 Jülich, Germany
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Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université de Paris, 13 rue Pierre et Marie Curie, F-75005 Paris, France
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Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, 75005 Paris, France
*
Authors to whom correspondence should be addressed.
Academic Editors: Marco Tutone and Anna Maria Almerico
Molecules 2021, 26(5), 1250; https://doi.org/10.3390/molecules26051250
Received: 11 December 2020 / Revised: 28 January 2021 / Accepted: 3 February 2021 / Published: 26 February 2021
The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein. View Full-Text
Keywords: hTSPO; PK11195; cholesterol; homology modeling; molecular dynamics (MD) simulation hTSPO; PK11195; cholesterol; homology modeling; molecular dynamics (MD) simulation
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MDPI and ACS Style

Lai, H.T.T.; Giorgetti, A.; Rossetti, G.; Nguyen, T.T.; Carloni, P.; Kranjc, A. The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations. Molecules 2021, 26, 1250. https://doi.org/10.3390/molecules26051250

AMA Style

Lai HTT, Giorgetti A, Rossetti G, Nguyen TT, Carloni P, Kranjc A. The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations. Molecules. 2021; 26(5):1250. https://doi.org/10.3390/molecules26051250

Chicago/Turabian Style

Lai, Hien T.T., Alejandro Giorgetti, Giulia Rossetti, Toan T. Nguyen, Paolo Carloni, and Agata Kranjc. 2021. "The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations" Molecules 26, no. 5: 1250. https://doi.org/10.3390/molecules26051250

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