<br/>The 18-KDa Translocator protein (TSPO) is an integral membrane protein located in the outer mitochondrial membrane. While its function remains unknown, TSPO’s protein expression has been observed to be upregulated in cases of neurological trauma and neurodegenerative diseases. This upregulation makes TSPO an attractive drug target to treat people with such conditions. Previous work has shown selective ligands with longer residence times (RT), not binding affinities, have a positive correlation with efficacy when bound to TSPO. To design new potential ligands that selectively bind to TSPO with long residence times, it is imperative to understand the unbinding pathways of existing ligands. This requires an atomistic model of the ligand (un)binding pathway which is (as yet) impossible to determine experimentally. Molecular Dynamics (MD) provides us the necessary resolution to hypothesize how ligands can dissociate from the TSPO, but is limited due to high energy barriers that separate the bound and unbound basins. Weighted ensemble, an enhanced sampling algorithm, has previously shown to be able to overcome such energy barriers. We use a weighted ensemble algorithm, Resampling of Ensembles by Variation Optimization (REVO) to unbind a TSPO selective ligand, PK11195 (PK), with a long residence time, approximately 34 minutes, from 6 different starting poses and predict the unbinding pathway in several independent simulations. We find that it dissociates into the lipid membrane through two different pathways. Each pathway has PK leave TSPO between two transmembrane (TM) α-helices. In the first pathway, it goes between TM1 and TM2 by forming aromatic ring stacking interactions between itself, Phe46 and Trp50. In the second pathway, it dissociates between TM2 and TM5 by interacting strongly with Trp135. We also calculated the residence time for each starting pose and compared it experimental residence times to determine the most likely starting pose.

Membrane mediated unbinding pathway for PK11195-TSPO system

ACS Fall 2020 Virtual Meeting

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