Insights into the Nature of Anesthetic–Protein
Interactions: An ONIOM Study
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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 <i>in vacuo</i>. 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