Rhodopsin is a highly efficient photoreceptor that, when excited by light, can activate the signaling pathway that leads to scotopic vision in mammals. This activation process requires the transduction of an external light stimulus across the membrane in which the protein is embedded via conformational changes. Experimental evidence has shown that rhodopsin's activity and structural stability is sensitive to the composition of its lipidic environment. However, the molecular mechanisms underlying this fine-tuned modulation are not fully understood. There are two hypotheses –often presented as mutually exclusive– that have been proposed to explain the nature of lipid effects on rhodopsin: 1) lipid modulation occurs via solvent-like interactions, where lipid composition controls membrane properties like hydrophobic thickness and acyl chain packing, which in turn modulate the protein's conformational equilibrium; or 2) lipid modulation occurs via ligand-like protein-lipid interactions, with specific hot spots and long-lived binding events. Here, we analyze an ensemble of microsecond-scale all-atom molecular dynamics simulations of rhodopsin in five different protein states to investigate the molecular details of lipid modulation in this receptor. Our simulations suggest that both solvent-like and ligand-like properties of lipids can influence rhodopsin’s structure and function. By comparing multiple protein states along the protein's photocycle, we show that a local reordering effect takes place in the membrane upon receptor activation (a solvent-like effect). Likewise, we find that lipids can behave like weak ligands, preferentially binding to the receptor in inactive-like protein conformations and inducing subtle but significant structural changes (a ligand-like effect).<br/>

Lipids alter rhodopsin function via solvent-like and ligand-like interactions

2019 Spring National Meeting

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