G Protein-Coupled Receptors Induce Domain Formation in Plasma Membrane Models Probed by Molecular Dynamics Simulations

Abstract

Lipid domains in plasma membranes are typically nanosized regions with a distinct lipid content. They have been suggested to have multiple functions. For example, the lipid environment can affect the activity of membrane proteins through direct lipid binding or by changing membrane properties. However, the detailed plasma membrane lipid organization and forces driving domain formation have remained elusive, since lipid domains are difficult to study due to their nanoscale size. In this thesis, we study the effects of three different G protein-coupled receptors (GPCRs) on the lateral and transmembrane lipid distributions. To this end, we use self-assembly through molecular dynamics (MD) simulations to study the lipid environment of the β_2-adrenergic receptor, the µ-opioid receptor, and rhodopsin proteins in plasma membrane models that account for the effect of 16 abundant lipid species. Our study reveals that GPCRs affect the lateral organization but not the transmembrane distribution of lipids. Polyunsaturated lipids and one monounsaturated lipid, phosphatidylinositol, are preferred to reside at the protein surface over other studied lipids. Thus, we conclude that GPCR proteins can induce domain formation in plasma membrane models. The results provide important insights into domain formation, which is important to better understand the functioning of GPCR proteins that are essential for human health.