Unsaturated Lipids Facilitate Partitioning of Transmembrane Peptides into the Liquid Ordered Phase

The affinity of single-passtransmembrane (TM) proteins for orderedmembrane phases has been reported to depend on their lipidation, TMlength, and lipid accessible surface area. In this work, the raftaffinities of the TM domain of the linker for activation of T cellsand its depalmitoylated variant are assessed using free energy simulationsin a binary bilayer system composed of two laterally patched bilayersof ternary liquid ordered (Lo) and liquid disordered (Ld) phases.These phases are modeled by distinct compositions of distearoylphosphatidylcholine,palmitoyloleoylphosphatidylcholine (POPC), and cholesterol, and thesimulations were carried out for 4.5 & mu;s/window. Both peptidesare shown to preferentially partition into the Ld phase in agreementwith model membrane experiments and previous simulations on ternarylipid mixtures but not with measurements on giant plasma membranevesicles where the Lo is slightly preferred. However, the 500 ns averagerelaxation time of lipid rearrangement around the peptide precludeda quantitative analysis of free energy differences arising from peptidepalmitoylation and two different lipid compositions. When in the Lophase, peptides reside in regions rich in POPC and interact preferentiallywith its unsaturated tail. Hence, the detailed substructure of theLo phase is an important modulator of peptide partitioning, in additionto the inherent properties of the peptide.

Automated summary

The affinity of TM proteins for ordered membrane phases is influenced by lipidation, TM length, and lipid accessible surface area. In this study, the raft affinities of a TM domain and its depalmitoylated variant were assessed using free energy simulations. The results showed that both peptides preferentially partition into the liquid disordered phase and the detailed substructure of the liquid ordered phase modulates peptide partitioning.