title: Insights into the Nature of Anesthetic-Protein Interactions: An ONIOM Study.
abstract: Anesthetics have been employed widely to relieve surgical suffering, but their mechanism of action is not yet clear. For over a century, the mechanism of anesthesia was previously thought to be via lipid bilayer interactions. In the present work, a rigorous three-layer ONIOM(M06-2X/6-31+G*:PM6:AMBER) method was utilized to investigate the nature of interactions between several anesthetics and actual protein binding sites. According to the calculated structural features, interaction energies, atomic charges, and electrostatic potential surfaces, the amphiphilic nature of anesthetic-protein interactions was demonstrated for both inhalational and injectable anesthetics. The existence of hydrogen and halogen bonding interactions between anesthetics and proteins was clearly identified, and these interactions served to assist ligand recognition and binding by the protein. Within all complexes of inhalational or injectable anesthetics, the polarization effects play a dominant role over the steric effects and induce a significant asymmetry in the otherwise symmetric atomic charge distributions of the free ligands in vacuo. This study provides new insight into the mechanism of action of general anesthetics in a more rigorous way than previously described. Future rational design of safer anesthetics for an aging and more physiologically vulnerable population will be predicated on this greater understanding of such specific interactions.
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine , Wuxi 214063, P. R. China.|Department of Anesthesia, Stanford University School of Medicine, Palo Alto VA Health Care System , 112A, PAVAHCS, 3801 Miranda Avenue, Palo Alto, California 94304, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine , Wuxi 214063, P. R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Palo Alto VA Health Care System , 112A, PAVAHCS, 3801 Miranda Avenue, Palo Alto, California 94304, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bertaccini
mesh_terms: D000777:Anesthetics / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
chemical_list: D000777:Anesthetics; D011506:Proteins