Complex, convoluted, yet consistent: Protein-induced membrane remodeling around GPCRs.

Abstract

Proteins embedded in cell membranes are the targets for ∼70% of all FDA-approved drugs. A single family of membrane proteins, called ‘GPCRs’ account for almost one third of all drug targets. These cell membranes are highly complicated environments, made up of many different types of constituent lipid molecules. Experimentally, the use of different types of lipids in the membrane that surrounds the protein is known to modulate the protein behavior. However, when designing or testing novel therapeutics, the influence of the membrane is often ignored; 50% of the environment is overlooked. Thus, studies carried out to optimize therapeutics can potentially be misleading - it is possible for the protein to respond differently depending on the properties of the membrane. Using novel multiscale simulations, and a sophisticated membrane model, we demonstrate just how complex and intricate the protein-lipid interaction are. Indeed, the property-altering interactions between the proteins and lipids are reciprocal. While lipids can induce changes in protein behavior, the protein can also drive either changes in lipid properties or reorganization of the lipids. The systems acclimatize and adjust to external stimuli to provide a more consistent, reliable environment for the protein to complete its function. The fine-tuning adaptation of the system further highlights the symbiotic nature of the membrane and the protein such that they should not be considered separate elements but treated as a single multicomponent drug target. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344 and was supported by the LLNL-LDRD Program under Project No. 21-ERD-047. LLNL-ABS-840667.