Noble gas binding to human serum albumin using docking simulation: nonimmobilizers and anesthetics bind to different sites.

BACKGROUND Nonimmobilizers are structurally similar to anesthetics, but do not produce anesthesia at clinically relevant concentrations. Xenon, krypton, and argon are anesthetics, whereas neon and helium are nonimmobilizers. The structures of noble gases with anesthetics or nonimmobilizers are similar and their interactions are simple. Whether the binding site of anesthetics differs from that of nonimmobilizers has long been a question in molecular anesthesiology. METHODS We investigated the binding sites and energies of anesthetic and nonimmobilizer noble gases in human serum albumin (HSA) because the 3D structure of HSA is well known and it has an anesthetic binding site. The computational docking simulation we used searches for binding sites and calculates the binding energy for small molecules and a template molecule. RESULTS Xenon, krypton, and argon were found to bind to the enflurane binding site of HSA, whereas neon and helium were found to bind to sites different from the xenon binding site. Rare gas anesthetic binding was dominated by van der Waals energy, while nonimmobilizer binding was dominated by solvent-effect energy. Binding site preference was determined by the ratios of local binding energy (van der Waals energy) and nonspecific binding energy (solvent-effect energy) to the total binding energy. van der Waals energy dominance is necessary for anesthetic binding. CONCLUSIONS This analysis of binding energy components provides a rationale for the binding site difference of anesthetics and nonimmobilizers, reveals the differences between the binding interactions of anesthetics and nonimmobilizers, may explain pharmacological differences between anesthetics and nonimmobilizers, and provide an understanding of anesthetic action at the atomic level.