Dataset Information

Menthol Binding to the Human ?4?2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane.

ABSTRACT: We utilize various computational methodologies to study menthol's interaction with multiple organic phases, a lipid bilayer, and the human ?4?2 nicotinic acetylcholine receptor (nAChR), the most abundant nAChR in the brain. First, force field parameters developed for menthol are validated in alchemical free energy perturbation simulations to calculate solvation free energies of menthol in water, dodecane, and octanol and compare the results against experimental data. Next, umbrella sampling is used to construct the free energy profile of menthol permeation across a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. The results from a flooding simulation designed to study the water-membrane partitioning of menthol in a POPC lipid bilayer are used to determine the penetration depth and the preferred orientation of menthol in the bilayer. Finally, employing both docking and flooding simulations, menthol is shown to bind to different sites on the human ?4?2 nAChR. The most likely binding mode of menthol to a desensitized membrane-embedded ?4?2 nAChR is identified to be via a membrane-mediated pathway in which menthol binds to the sites at the lipid-protein interface after partitioning in the membrane. A rare but distinct binding mode in which menthol binds to the extracellular opening of receptor's ion permeation pore is also reported.

SUBMITTER: Shahoei R

PROVIDER: S-EPMC7094167 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Menthol Binding to the Human α4β2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane.

Shahoei Rezvan R Tajkhorshid Emad E

The journal of physical chemistry. B 20200302 10

We utilize various computational methodologies to study menthol's interaction with multiple organic phases, a lipid bilayer, and the human α4β2 nicotinic acetylcholine receptor (nAChR), the most abundant nAChR in the brain. First, force field parameters developed for menthol are validated in alchemical free energy perturbation simulations to calculate solvation free energies of menthol in water, dodecane, and octanol and compare the results against experimental data. Next, umbrella sampling is u ...[more]

PMID: 32048843

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Project description:Nicotine, the principal reinforcing compound in tobacco, acts in the brain by activating neuronal nicotinic acetylcholine receptors (nAChRs). This review summarizes our current knowledge regarding how the α5 accessory nAChR subunit, encoded by the CHRNA5 gene, differentially modulates α4β2* and α3β4* receptors at the cellular level. Genome-wide association studies have linked a gene cluster in chromosomal region 15q25 to increased susceptibility to nicotine addiction, lung cancer, chronic obstructive pulmonary disease, and peripheral arterial disease. Interestingly, this gene cluster contains a non-synonymous single-nucleotide polymorphism (SNP) in the human CHRNA5 gene, causing an aspartic acid (D) to asparagine (N) substitution at amino acid position 398 in the α5 nAChR subunit. Although other SNPs have been associated with tobacco smoking behavior, efforts have focused predominantly on the D398 and N398 variants in the α5 subunit. In recent years, significant progress has been made toward understanding the role that the α5 nAChR subunit-and the role of the D398 and N398 variants-plays on nAChR function at the cellular level. These insights stem primarily from a wide range of experimental models, including receptors expressed heterologously in Xenopus oocytes, various cell lines, and neurons derived from human induced pluripotent stem cells (iPSCs), as well as endogenous receptors in genetically engineered mice and-more recently-rats. Despite providing a wealth of available data, however, these studies have yielded conflicting results, and our understanding of the modulatory role that the α5 subunit plays remains incomplete. Here, we review these reports and the various techniques used for expression and analysis in order to examine how the α5 subunit modulates key functions in α4β2* and α3β4* receptors, including receptor trafficking, sensitivity, efficacy, and desensitization. In addition, we highlight the strikingly different role that the α5 subunit plays in Ca2+ signaling between α4β2* and α3β4* receptors, and we discuss whether the N398 α5 subunit variant can partially replace the D398 variant.

Dataset Information

Menthol Binding to the Human ?4?2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane.

Publications

Menthol Binding to the Human α4β2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane.

Similar Datasets

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