Membrane-mediated ligand unbinding of the PK-11195 ligand from the translocator protein (TSPO)

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 transmembrane helices. We analyze this path ensemble in detail, constructing descriptors that can facilitate a general understanding of membrane-mediated ligand binding.