First principles predictions of the structure and activity of Olfactory Receptors
Wely B. Floriano†, Nagarajan Vaidehi †, Michael S. Singer‡, Gordon M. Shepherd‡ and William A. Goddard III†‚*
†Materials and Process Simulation Center, Beckman Institute (139-74), California Institute of Technology, Pasadena, CA 91125
‡Section of Neurobiology, Yale University School of Medicine, New Haven, CT
In order to provide a framework for the long-awaited in silico approach to receptor characterization, we have predicted the structure for the olfactory receptor (OR) S25, the structure for alcohols bound to this OR, and the absolute binding energy for 24 odour compounds bound to this site. Since no crystal structure is available for ORs, we derived an atomic-level structural model for mouse ORS251 by combining the density map of rhodopsin2 with recently developed first principles molecular dynamics (MD) methods3-12. The predicted atomic-level structure for ORS25 was used in docking13 and MD studies3 to predict the binding pocket and binding energies for 24 odour compounds tested by Malnic et al.1. No experimental data were used to predict this binding site. The two odour molecules predicted to bind most avidly were precisely the two observed experimentally to activate this receptor . This is the first molecular model to predict correctly the differential responses of a receptor to a broad panel of agonists. This model suggests mutation and binding experiments on S25.
Our developed modeling and docking protocol is intended to be general for other G-Protein coupled Receptors (GPCRs). Besides the sequence, the only additional information required for modeling are sequence alignment of other GPCRs and the bovine rhodopsin electron density map. The combined protocols are currently being used to predict the binding site(s) of ORS19.
We thank Linda Buck and Bettina Malnic for sharing results prior to publication and for helpful comments. We also thank ARO (Multidisciplinary University Research Initiative, Dr. Robert Campbell) for support of this collaborative effort. The facilities of the Materials and Process Simulation Center used in this project are supported also by DOE (ASCI ASAP), NSF (CHE and MRI), ARO, Chevron Corp., MMM, Beckman Institute, Seiko-Epson, Exxon, Dow Chemical, Avery-Dennison Corp., NASA, NIH HD(WAG), Asahi Chemical, and BP Chemical. This work is also supported by NIDCD (GMS); NIDCD, NIA, NASA, and NIMH (Human Brain Project, GMS); Yale MSTP (MSS); and NIMH (IAIMS, MSS).
Figure 1. Predicted structure for Mouse Olfactory Receptor S25 with predicted binding site of hexanol (purple). The membrane is represented by a barrel of dilauroylphosphatidyl choline bilayers (yellow) surrounding the transmembrane domains (TMs) 1 to 7.
Figure 2. Calculated Binding Energies for 24 odorants docked to the mouse Olfactory Receptor S25. Binding Energy bars are shaded according to the chemical classes indicated above them. The letter C followed by a number indicates the number of carbon atoms. The binding energies were calculated as the difference between the energy of the ligand in protein and in solution. The solvation corrections were calculated using Poisson-Boltzmann continuum model for the solvent. The energies were calculated using DREIDING FF4. Hexanol and Heptanol (marked with asterisks in the figure) are the only two compounds of the 24 found experimentally to elicit responses1. These compunds are correctly predicted by our model as having the most favorable Binding Energies. The solution phase energy was based on dynamics staring with the bound conformation and hence is an upper bound.