The thermodynamics of ligand binding has been of intense interest for decades due to its importance in the rational design of new drug molecules.  More recently, it has been appreciated that the kinetics of ligand binding is – for some systems – more useful than thermodynamics to predict therapeutic effect <i>in vivo</i>.  The rational design of new compounds on the basis of kinetics is more challenging, as it requires knowledge not just of the end states, but of the pathway by which ligands bind.  In recent years we and other groups have shown that simulation, employing rare event methods, can elucidate structural features along binding pathways.  Here we study the ligand PK-11195, which is used in positron emission tomography (PET) scans of brain tissue to assess neuronal damage and visualize brain inflammation.  In these applications, PK-11195 binds potently and selectively to the membrane protein TSPO (mitochondrial 18 kDa translocator protein).  Although the biological role of TSPO is unknown, it has been shown that TSPO inhibition can aid the production of neurosteroids, and that the strength of this effect correlates with the TSPO inhibitor residence time.  To determine the molecular factors that govern residence time and aid kinetics-oriented drug design in this area, we simulated an ensemble of ligand release pathways of the PK-11195 ligand from TSPO - a process with an experimental mean first passage time of 33 min.  We find that PK-11195 is a hydrophobic ligand that significantly partitions into the membrane.  Further, we predict that all binding and unbinding processes are mediated by a membrane-solvated state.  We analyze this pathway ensemble in detail and construct a set of general descriptors that can be used to analyze all ligand binding pathways that pass through pairs of transmembrane helices.

Membrane-mediated ligand binding pathway of the TSPO-ligand PK-11195

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.