How membrane receptors and lipids adapt to hydrophobic mismatch: a computational study of β2-adrenergic receptor in membranes of varying thickness

Abstract

Study of lipid-protein interactions has gained lots of scientific interest in the recent years. It is well known that the lipid environment can have a huge effect on the function of many membrane proteins and that defects in their functions can lead to various diseases and malfunctions. Specifically, the matching of the hydrophobic thicknesses of membrane proteins and lipids has turned out to be biologically important in this aspect. In this thesis the effects of hydrophobic mismatch on a G-protein coupled receptor (GPCR) and the surrounding lipid membrane was studied. The study was conducted by producing a set of molecular dynamics simulations where the GPCR β2-adrenergic receptor is embedded in lipid bilayers of different thicknesses. The bilayers considered in this study consisted of unsaturated phosphatidylcholine lipids or of both unsaturated phosphatidylcholine lipids and cholesterol molecules. The simulations help to predict the mechanisms by which membrane receptors and lipids are able to adapt to hydrophobic mismatch. The simulations show that the receptor affects the thickness profile of the lipid bilayer by inducing changes in the lipid tail conformation and that it also has an influence on the distribution of cholesterol molecules in the bilayer. Furthermore, they show what kind of changes there are in the conformation and orientation of β2 -adrenergic receptor that help the receptor to adapt to hydrophobic mismatch.