A molecular description of how noble gases and nitrogen bind to a model site of anesthetic action.
How some noble and diatomic gases produce anesthesia remains unknown. Although these gases have apparently minimal capacities to interact with a putative anesthetic site, xenon is a clinical anesthetic, and argon, krypton, and nitrogen produce anesthesia at hyperbaric pressures. In contrast, neon, helium, and hydrogen do not cause anesthesia at partial pressures up to their convulsant thresholds. We propose that anesthetic sites influenced by noble or diatomic gases produce binding energies composed of London dispersion and charge-induced dipole energies that are sufficient to overcome the concurrent unfavorable decrease in entropy that occurs when a gas molecule occupies the site. To test this hypothesis, we used the x-ray diffraction model of the binding site for Xe in metmyoglobin. This site offers a positively charged moiety of histidine 93 that is 3.8 A from Xe. We simulated placement of He, Ne, Ar, Kr, Xe, H2, and N2 sequentially at this binding site and calculated the binding energies, as well as the repulsive entropy contribution. We used free energies obtained from tonometry experiments to validate the calculated binding energies. We used partial pressures of gases that prevent response to a noxious stimulus (minimum alveolar anesthetic concentration [MAC]) as the anesthetic endpoint. The calculated binding energies correlated with binding energies derived from the in vivo (ln) data (RTln[MAC], where R is the gas constant and T is absolute temperature) with a slope near 1.0, indicating a parallel between the Xe binding site in metmyoglobin and the anesthetic site of action of noble and diatomic gases. Nonimmobilizing gases (Ne, He, and H2) could be distinguished by an unfavorable balance between binding energies and the repulsive entropy contribution. These gases also differed in their inability to displace water from the cavity.


CONCLUSIONS
The Xe binding site in metmyoglobin is a good model for the anesthetic sites of action of noble and diatomic gases. The additional binding energy provided by induction of a dipole in the gas by a charge at the binding site enhanced binding.
Department of Anesthesia, Program for Molecular and Genetic Medicine, Stanford School of Medicine, California, USA.
J R
JR
Trudell
D D
DD
Koblin
E I
EI
Eger
D000777:Anesthetics / Q000378:metabolism*; D001665:Binding Sites; D008786:Metmyoglobin / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*; D005741:Noble Gases / Q000737:chemistry / Q000378:metabolism*; D010313:Partial Pressure; D011485:Protein Binding; D013816:Thermodynamics; D014978:Xenon / Q000378:metabolism
D000777:Anesthetics; D005741:Noble Gases; D008786:Metmyoglobin; D014978:Xenon; D009584:Nitrogen