Volatile anesthetic binding to proteins is influenced by solvent and aliphatic residues.
The main objective of this work was to characterize VA binding sites in multiple anesthetic target proteins. A computational algorithm was used to quantify the solvent exclusion and aliphatic character of amphiphilic pockets in the structures of VA binding proteins. VA binding sites in the protein structures were defined as the pockets with solvent exclusion and aliphatic character that exceeded minimum values observed in the VA binding sites of serum albumin, firefly luciferase, and apoferritin. We found that the structures of VA binding proteins are enriched in these pockets and that the predicted binding sites were consistent with experimental determined binding locations in several proteins. Autodock3 was used to dock the simulated molecules of 1,1,1,2,2-pentafluoroethane, difluoromethyl 1,1,1,2-tetrafluoroethyl ether, and sevoflurane and the isomers of halothane and isoflurane into these potential binding sites. We found that the binding of the various VA molecules to the amphiphilic pockets is driven primarily by VDW interactions and to a lesser extent by weak hydrogen bonding and electrostatic interactions. In addition, the trend in Delta G binding values follows the Meyer-Overton rule. These results suggest that VA potencies are related to the VDW interactions between the VA ligand and protein target. It is likely that VA bind to sites with a high degree of solvent exclusion and aliphatic character because aliphatic residues provide favorable VDW contacts and weak hydrogen bond donors. Water molecules occupying these sites maintain pocket integrity, associate with the VA ligand, and diminish the unfavorable solvation enthalpy of the VA. Water molecules displaced into the bulk by the VA ligand may provide an additional favorable enthalpic contribution to VA binding. Anesthesia is a component of many health related procedures, the outcomes of which could be improved with a better understanding of the molecular targets and mechanisms of anesthetic action.
Streiff
John H
JH
Department of Anesthesiology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294-1150, USA. jstreiff@uab.edu
Jones
Keith A
KA
D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D004350:Drug Residues / Q000737:chemistry / Q000378:metabolism*; D004735:Energy Transfer; D006838:Hydrocarbons / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry; D012997:Solvents; D013329:Structure-Activity Relationship
D018685:Anesthetics, Inhalation; D006838:Hydrocarbons; D008024:Ligands; D011506:Proteins; D012997:Solvents