biostudies-literatureElisi GMCINECAMinistero dell'Istruzione, dell'Universit?? e della Ricerca210-222https://www.ebi.ac.uk/biostudies/studies/S-EPMC8757440biostudies-literatureUnknown62(1)The effects of the neurohormone melatonin are mediated by the activation of the GPCRs MT₁ and MT₂ in a variety of tissues. Crystal structures suggest ligand access to the orthosteric binding site of MT₁ and MT₂ receptors through a lateral channel between transmembrane (TM) helices IV and V. We investigated the feasibility of this lipophilic entry route for 2-iodomelatonin, a nonselective agonist with a slower dissociation rate from the MT₂ receptor, applying enhanced sampling simulations and free-energy calculations. 2-Iodomelatonin unbinding was investigated with steered molecular dynamics simulations which revealed different trajectories passing through the gap between TM helices IV and V for both receptors. For one of these unbindinJournal of chemical information and modelingFree-Energy Simulations Support a Lipophilic Binding Route for Melatonin Receptors.PMC8757440HP10CB3GC3HP10CI4MQB20175SA5JJRivara SLodola AScalvini LMor MElisi GMfalseFree-Energy Simulations Support a Lipophilic Binding Route for Melatonin Receptors.The effects of the neurohormone melatonin are mediated by the activation of the GPCRs MT₁ and MT₂ in a variety of tissues. Crystal structures suggest ligand access to the orthosteric binding site of MT₁ and MT₂ receptors through a lateral channel between transmembrane (TM) helices IV and V. We investigated the feasibility of this lipophilic entry route for 2-iodomelatonin, a nonselective agonist with a slower dissociation rate from the MT₂ receptor, applying enhanced sampling simulations and free-energy calculations. 2-Iodomelatonin unbinding was investigated with steered molecular dynamics simulations which revealed different trajectories passing through the gap between TM helices IV and V for both receptors. For one of these unbindin2022-01-01T00:00:00Z2022 Jan2026-05-09T05:58:45.288Z2022-02-11T16:20:46.486ZS-EPMC87574403493232910.1021/acs.jcim.1c01183