The molecular mechanism of action underlying general anesthesia remains a matter of controversy. One proposed mode of action involves binding of anesthetic molecules to membrane proteins such as ligand gated ion channels, thereby modulating their function. An alternative mode of action discussed in the literature is through binding to the lipid bilayer. We chose to explore both modes of action at the molecular level by studying two types of targets: pure lipid bilayer systems such as POPC, and a lipid bilayer with the pentameric ligand-gated ion channel GLIC inserted into it. Sauguet et al. recently solved the structure of GLIC in complex with the general anesthetic Xenon [1], describing a multitude of binding sites. Here, we studied the effect of a series of three Noble gases: Argon, Krypton and Xenon. We have performed molecular dynamics (MD) simulations to gain key insights on the Noble gases binding location and affinity. Different gas:lipid ratios were used to characterize their effect on the physical properties of the membrane, as well as their affinity for the core of the lipid bilayer. Microsecond-long flooding simulations, combined with free energy calculations, were run to characterize access to binding sites and quantify binding affinities of Nobles Gases on the GLIC channel. This work extends and generalizes our previous study on bromoform action on GLIC, that revealed a complex network of interconnected binding sites, possibly all contributing in concert to the anesthetic effect [2]. We go beyond previous work by considering the measurable effect on lipid bilayer properties induced by the Noble gases therefore providing a better description of key pathways for anesthetic action. [1] Sauguet et al. Plos One. 2016. doi: 10.1371/ journal.pone.0149795 [2] Laurent, Murail et al. Structure. 2016. doi: 10.1016/j.str.2016.02.014