title: Gated narrow escape time for molecular signaling.
abstract: The mean time for a diffusing ligand to activate a target protein located on the surface of a microdomain can regulate cellular signaling. When the ligand switches between various states induced by chemical interactions or conformational changes, while target activation occurs in only one state, this activation time is affected. We investigate this dynamics using new equations for the sojourn times spent in each state. For two states, we obtain exact solutions in dimension one, and asymptotic ones confirmed by Brownian simulations in dimension 3. We find that the activation time is quite sensitive to changes of the switching rates, which can be used to modulate signaling. Interestingly, our analysis reveals that activation can be fast although the ligand spends most of the time "hidden" in the nonactivating state. Finally, we obtain a new formula for the narrow escape time in the presence of switching.
authors.affiliation: Department of Computational Biology, Ecole Normale Supérieure, 46 rue d'Ulm 75005 Paris, France.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Reingruber
authors.forename: David
authors.initials: D
authors.lastname: Holcman
mesh_terms: D004058:Diffusion; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D008024:Ligands; D011506:Proteins