G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs. Here, using free energy techniques and multiscale simulations of numerous membrane proteins, we show that the presence of the PUFA DHA helps helical multi-pass proteins such as GPCRs partition into ordered membrane domains. The mechanism is based on hybrid lipids, whose PUFA chains coat the rough protein surface, while the saturated chains face the raft environment, thus minimizing perturbations therein. Our findings suggest that the reduction of GPCR partitioning to their native ordered environments due to PUFA depletion might affect the function of these receptors in numerous neurodegenerative diseases, where the membrane PUFA levels in the brain are decreased. We hope that this work inspires experimental studies on the connection between membrane PUFA levels and GPCR signaling.

Computational Physics Laboratory Tampere University Tampere Finland Department of Physics University of Helsinki Helsinki Finland

Computational Physics Laboratory Tampere University Tampere Finland Department of Physics University of Helsinki Helsinki Finland Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Computational Physics Laboratory Tampere University Tampere Finland Department of Physics University of Helsinki Helsinki Finland MEMPHYS Center for Biomembrane Physics

Department of Integrated Biology and Pharmacology McGovern Medical School University of Texas Health Science Center at Houston Houston United States of America

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Computational Medicine Biostatistics Unit Faculty of Medicine Autonomous University of Barcelona Bellaterra Spain

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