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Lipids Alter Rhodopsin Function via Ligand-like and Solvent-like Interactions.

ABSTRACT: Rhodopsin, a prototypical G protein-coupled receptor, is a membrane protein that can sense dim light. This highly effective photoreceptor is known to be sensitive to the composition of its lipidic environment, but the molecular mechanisms underlying this fine-tuned modulation of the receptor's function and structural stability are not fully understood. There are two competing hypotheses to explain how this occurs: 1) lipid modulation occurs via solvent-like interactions, where lipid composition controls membrane properties like hydrophobic thickness, which in turn modulate the protein's conformational equilibrium; or 2) protein-lipid interactions are ligand-like, with specific hot spots and long-lived binding events. By analyzing an ensemble of all-atom molecular dynamics simulations of five different states of rhodopsin, we show that a local ordering effect takes place in the membrane upon receptor activation. Likewise, docosahexaenoic acid acyl tails and phosphatidylethanolamine headgroups behave like weak ligands, preferentially binding to the receptor in inactive-like conformations and inducing subtle but significant structural changes.

SUBMITTER: Salas-Estrada LA

PROVIDER: S-EPMC5984976 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Lipids Alter Rhodopsin Function via Ligand-like and Solvent-like Interactions.

Salas-Estrada Leslie A LA Leioatts Nicholas N Romo Tod D TD Grossfield Alan A

Biophysical journal 20180101 2

Rhodopsin, a prototypical G protein-coupled receptor, is a membrane protein that can sense dim light. This highly effective photoreceptor is known to be sensitive to the composition of its lipidic environment, but the molecular mechanisms underlying this fine-tuned modulation of the receptor's function and structural stability are not fully understood. There are two competing hypotheses to explain how this occurs: 1) lipid modulation occurs via solvent-like interactions, where lipid composition ...[more]

PMID: 29401433

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Project description:The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known, however, that the presence of anionic lipids in cell membranes is one of the important factors determining CT-membrane binding. In this work, we therefore investigated specific interactions between one of the most abundant of such lipids, phosphatidylserine (PS), and CT 4 of Naja kaouthia using a combined, experimental and modeling, approach. It was shown that incorporation of PS into zwitterionic liposomes greatly increased the membrane-damaging activity of CT 4 measured by the release of the liposome-entrapped calcein fluorescent dye. The CT-induced leakage rate depends on the PS concentration with a maximum at approximately 20% PS. Interestingly, the effects observed for PS were much more pronounced than those measured for another anionic lipid, sulfatide. To delineate the potential PS binding sites on CT 4 and estimate their relative affinities, a series of computer simulations was performed for the systems containing the head group of PS and different spatial models of CT 4 in aqueous solution and in an implicit membrane. This was done using an original hybrid computational protocol implementing docking, Monte Carlo and molecular dynamics simulations. As a result, at least three putative PS-binding sites with different affinities to PS molecule were delineated. Being located in different parts of the CT molecule, these anion-binding sites can potentially facilitate and modulate the multi-step process of the toxin insertion into lipid bilayers. This feature together with the diverse binding affinities of the sites to a wide variety of anionic targets on the membrane surface appears to be functionally meaningful and may adjust CT action against different types of cells.

Dataset Information

Lipids Alter Rhodopsin Function via Ligand-like and Solvent-like Interactions.

Publications

Lipids Alter Rhodopsin Function via Ligand-like and Solvent-like Interactions.

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