Abstract
The translocation of lipids across membranes (flip-flop) is an important biological process. Slow exchange on a physiological timescale allows the creation of asymmetric distributions of lipids across cellular membranes. The location of lipids and their rate of exchange have important biological consequences, especially for lipids involved in cellular signaling. We investigated the translocation of cholesterol, ceramide, and diacylglycerol in two model bilayers using molecular dynamics simulations. We estimate half times for flip-flop for cholesterol, diacylglycerol, and ceramide of 20 μs, 30 μs, and 10 ms in a POPC bilayer, compared with approximately 30 min, 30 ms, and 30 s in a model raft bilayer (1:1:1 PSM, POPC, and cholesterol). Cholesterol has a large (54 kJ/mol) free energy of exchange between the POPC and raft bilayer, and therefore, it strongly prefers the more ordered and rigid raft bilayer over the more liquid POPC bilayer. Ceramide and diacylglycerol have relatively small free energies of exchange, suggesting nearly equal preference for both bilayers. This unexpected result may have implications for ceramide and diacylglycerol signaling and membrane localization.
Highlights
The translocation of lipids across membranes is an important biological process
Cholesterol has a strong preference for the Raft bilayer compared with the POPC bilayer, with a Gex of 54 kJ/mol
On the subnanometer length scale, we discovered some of the specific molecular determinants for the underlying free energy profile, including hydrogen bonds, lipid membrane perturbations, and molecular geometry
Summary
We simulated two model bilayers: pure POPC (64 POPC) and a 1:1:1 mixture of PSM, cholesterol, and POPC (22 lipids each) as a model Raft bilayer. In the Raft bilayer, both lipids have a deep trough in the head-to-tail distance at approximately 1 nm from the bilayer center, which suggests a compact conformation at this position This distance corresponds to the free energy barrier for flip-flop (Fig. 3). Ceramide and diacylglycerol show prominent drops in the head-to-tail distance as they stop interacting with the bilayer (Fig. 6) This is illustrated by the change in average angle from approximately 20° to 90° (Fig. 6), the angle distributions for the Raft bilayer at 3.8 nm and 4.3 nm from the bilayer center (Fig. 7B), and the corresponding snapshots (Fig. 5F, G).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
