%0 Journal Article %1 Dixon2020TSPOLigandUnbinding %A Dixon, Tom %A Uyar, Arzu %A Ferguson-Miller, Shelagh %A Dickson, Alex %D 2020 %I Cold Spring Harbor Laboratory %J bioRxiv %K ligand-unbinding wepy %R 10.1101/2020.01.21.914127 %T Membrane-mediated ligand unbinding of the PK-11195 ligand from the translocator protein (TSPO) %U https://www.biorxiv.org/content/early/2020/01/21/2020.01.21.914127 %X The translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is of longstanding medical interest as both a biomarker for neuroinjury and a potential drug target for neuroinflammation and other disorders. Recently it was shown that ligand residence time is a key factor determining steroidogenic efficacy of TSPO-binding compounds. This spurs interest in simulations of (un)binding pathways of TSPO ligands, which could reveal the molecular interactions governing ligand residence time. In this study, we use a weighted ensemble algorithm to determine the unbinding pathway for different poses of PK-11195, a TSPO ligand used in neuroimaging. In contrast with previous studies, our results show that PK-11195 does not dissociate directly into solvent but instead dissociates via the lipid membrane by going between the trans-membrane helices. We analyze this path ensemble in detail, constructing descriptors that can facilitate a general understanding of membrane-mediated ligand binding.

@article{Dixon2020TSPOLigandUnbinding, abstract = {The translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is of longstanding medical interest as both a biomarker for neuroinjury and a potential drug target for neuroinflammation and other disorders. Recently it was shown that ligand residence time is a key factor determining steroidogenic efficacy of TSPO-binding compounds. This spurs interest in simulations of (un)binding pathways of TSPO ligands, which could reveal the molecular interactions governing ligand residence time. In this study, we use a weighted ensemble algorithm to determine the unbinding pathway for different poses of PK-11195, a TSPO ligand used in neuroimaging. In contrast with previous studies, our results show that PK-11195 does not dissociate directly into solvent but instead dissociates via the lipid membrane by going between the trans-membrane helices. We analyze this path ensemble in detail, constructing descriptors that can facilitate a general understanding of membrane-mediated ligand binding.}, added-at = {2020-02-25T22:29:33.000+0100}, author = {Dixon, Tom and Uyar, Arzu and Ferguson-Miller, Shelagh and Dickson, Alex}, biburl = {https://www.bibsonomy.org/bibtex/2585f63fac4f8ed5ad3c9582b6fc81400/salotz}, description = {Membrane-mediated ligand unbinding of the PK-11195 ligand from the translocator protein (TSPO) | bioRxiv}, doi = {10.1101/2020.01.21.914127}, elocation-id = {2020.01.21.914127}, eprint = {https://www.biorxiv.org/content/early/2020/01/21/2020.01.21.914127.full.pdf}, interhash = {94959a98f556e959f738ea0ae73cfb5b}, intrahash = {585f63fac4f8ed5ad3c9582b6fc81400}, journal = {bioRxiv}, keywords = {ligand-unbinding wepy}, publisher = {Cold Spring Harbor Laboratory}, timestamp = {2020-02-25T22:29:33.000+0100}, title = {Membrane-mediated ligand unbinding of the PK-11195 ligand from the translocator protein (TSPO)}, url = {https://www.biorxiv.org/content/early/2020/01/21/2020.01.21.914127}, year = 2020 }