General anesthetics have, arguably, been one of the most important advances in modern medicine. Yet despite well over a century of research, the mechanism of general anesthesia is still poorly understood, although the molecular target of these drugs has recently been discovered. Recent crystal structures of bacterial homologues with anesthetics bound has made the problem more tractable to molecular dynamics. However, the lack of a widely available and reliable set of parameters for common anesthetics has impeded progress. Utilizing the standard CHARMM scheme, we have parameterized four commonly used modern anesthetics, namely desflurane, isoflurane, sevoflurane, and propofol. The generated parameters agree well with experimental bulk (density, ?Hvap) and solvation (?Gsolv in water and in oil) properties. In order to better understand how these anesthetics interact with membranes, we calculated the free energy profile for inserting each anesthetic into a POPC membrane utilizing the umbrella sampling method. All anesthetics show a distinct preference for the headgroup or interfacial region of the membrane, with negligible free energy differences between bulk solution and the membrane core. Using the parameters developed, we also simulated the interaction of desflurane and propofol with GLIC. In both cases, the anesthetic spontaneously releases from its binding site and exits the protein via the membrane in a reproducible manner. Additionally, �flooding� simulations, in which a large number of anesthetics are randomly placed in aqueous solution around the protein, reveal a pathway common to binding and unbinding. Several bulky residues at the membrane interface force the anesthetic to climb a 4 kcal/mol energetic barrier in order to bind and unbind the protein. These studies could impact the manner in which we design novel anesthetics with improved efficacy and safety.

Identifying a membrane-dependent pathway for anesthetic binding in ligand-gated ion channels

246th National Meeting (2013)

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