Noble Gas Anesthetics and Immobilizers Show Different Binding Distributions to KcsA Channel

Abstract

Neuronal ion channel is prominent candidate of molecular target anesthesia, but still not yet identified. Using KcsA potassium ion channel as model, anesthetic-protein interactions are investigated. We choose xenon, krypton and argon as anesthetics, which have simple structure. Neon and helium were also studied, which are structurally similar to anesthetics but do not have the anesthetic effects predicted by the Overton-Meyer rule (nonimmobilizers). Using computer simulation these binding sites of KcsA are searched. From the noble gas-KcsA complex structure we discuss binding characteristics of anesthetic and nonimmobilizer. Methods: 1k4c (PDB) was used as KcsA structure. Cavities in KcsA was searched with alpha-site finder (geometric search) in Molecular Operating Environment 2007.0902 (MOE, Chemical Computing Group, Canada), that is candidates of binding site of noble gas. Obtained dummy atom from alpha-site finder was used as initial position. Noble gas binding position was searched with energy minimization around initial position. MMFF94x was used for forcefield. Results: Binding energy of Xe, Kr, Ar were -8 to -4 kcal mol−1, whereas Ne and He were -2 kcal mol−1. Xe, Kr, Ar bound to gating region first, then they distributed to inter-helical space of transmembrane region. Ne bound to inter-helical space first, then to the gating region. Energy gaps of inter-helical sites were small, so noble gas was consider to be possible to transit from site to site with thermal energy. We considered that inter-helical binding have small position specificity (nospecific binding). Ne and He binding distributed inter-helical sites, the energy gaps were further small. They showed nonspecific binding. Anesthetics and nonimmobilizers of noble gases show different binding distribution to KcsA. We speculate that pharmacological difference of anesthetic and nonimmobilizer originates from the difference in binding distribution of these substances.