At least three xenon binding sites in the glycine binding domain of the N-methyl D-aspartate receptor

TL;DR

This study identifies three xenon binding sites in the glycine binding domain of the NMDA receptor through molecular dynamics simulations, shedding light on how xenon may exert its anesthetic effects at the molecular level.

Contribution

The paper reports the discovery of three xenon binding sites in the NMDA receptor's glycine domain using molecular dynamics, providing new insights into xenon's molecular mechanism of action.

Findings

Three xenon binding sites identified in the glycine domain.

Binding free energies range from -8 to -14 kJ/mol.

Binding sites are adjacent, explaining mutation effects on xenon inhibition.

Abstract

Xenon can produce general anesthesia. Its main protein target is the N-methyl-D-aspartate receptor, a ionotropic channel playing a pivotal role in the function of the central nervous system. The molecular mechanisms allowing this noble gas to have such a specific effect remain obscure, probably as a consequence of the lack of structural data at the atomic level of detail. Herein, as a result of five independent molecular dynamics simulations, three different binding sites were found for xenon in the glycine binding domain of the N-methyl-D-aspartate receptor. The absolute binding free energy of xenon in these sites ranges between -8 and -14 kJ/mole. However, it depends significantly upon the protein conformer chosen for performing the calculation, suggesting that larger values could probably be obtained, if other conformers were considered. These three sites are next to each other, one of them being next to the glycine site. This could explain why the F758W and F758Y mutations can prevent competitive inhibition by xenon without affecting glycine binding.