Chemical Senses Advance Access originally published online on October 21, 2005
Chemical Senses 2005 30(9):781-792; doi:10.1093/chemse/bji070
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Structural Activation Pathways from Dynamic Olfactory Receptor–Odorant Interactions
1 Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA, 2 Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA and 3 Department of Neurobiology and Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, CT, USA
Correspondence to be sent to: Chiquito Crasto, Department of Neurobiology and Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, CT, USA. e-mail: chiquito.crasto{at}yale.edu
We have simulated an odor ligand's dynamic behavior in the binding region of an olfactory receptor (OR). Our short timescale computational studies (up to 200 ps) have helped identify unprecedented postdocking ligand behavior of ligands. From in vacuo molecular dynamics simulations of interactions between models of rat OR I7 and 10 aldehyde ligands, we have identified a dissociative pathway along which the ligand exits and enters the OR-binding pocket—a transit event. The ligand's transit through the receptor's binding region may mark the beginning of a signal transduction cascade leading to odor recognition. We have graphically traced the rotameric changes in key OR amino acid side chains during the transit. Our results have helped substantiate or refute previously held notions of amino acid contribution to ligand stability in the binding pocket. Our observations of ligand activity when compared to those of experimental (electroolfactogram response) OR-activation studies provide a view to predicting the stability of ligands in the binding pocket as a precursor to OR activation by the ligand.
Key words: ligand binding, molecular dynamics, olfactory receptors
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