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 wi th a putative anesthetic site, xenon is a clinical anesthetic, and arg on, krypton, and nitrogen produce anesthesia at hyperbaric pressures. In contrast, neon, helium, and hydrogen do not cause anesthesia at par tial pressures up to their convulsant thresholds. We propose that anes thetic sites influenced by noble or diatomic gases produce binding ene rgies composed of London dispersion and charge-induced dipole energies that are sufficient to overcome the concurrent unfavorable decrease i n entropy that occurs when a gas molecule occupies the site. To test t his hypothesis, we used the x-ray diffraction model of the binding sit e for Xe in metmyoglobin. This site offers a positively charged moiety of histidine 93 that is 3.8 Angstrom, from Xe. We simulated placement of He, Ne, Ar, Kr, Xe, H-2, and N-2 sequentially at this binding site and calculated the binding energies, as well as the repulsive entropy contribution. We used free energies obtained from tonometry experimen ts to validate the calculated binding energies. We used partial pressu res of gases that prevent response to a noxious stimulus (minimum alve olar anesthetic concentration [MAC]) as the anesthetic endpoint. The c alculated binding energies correlated with binding energies derived fr om 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 o f action of noble and diatomic gases. Nonimmobilizing gases (Ne, He, a nd H-2) could be distinguished by an unfavorable balance between bindi ng energies and the repulsive entropy contribution. These gases also d iffered in their inability to displace water from the cavity. Implicat ions: The Xe binding site in metmyoglobin is a good model for the anes thetic sites of action of noble and diatomic gases. The additional bin ding energy provided by induction of a dipole in the gas by a charge a t the binding site enhanced binding.