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Molecular Simulations of Lipid Flip-Flop in the Presence of Model Transmembrane Helices

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Department of Biological Sciences, University of Calgary, 2500 University Drive, Calgary, Alberta T2N 1N4, Canada
*Corresponding author: e-mail, [email protected]; phone, 403-220-2966; fax, 403-289-9311.
‡Present address: CERMAV, UPR5301 CNRS, Institut de Chimie Moléculaire de Grenoble, Université de Grenoble, 601 rue de la chimie, BP 53, 38041 Grenoble, France
Cite this: Biochemistry 2010, 49, 35, 7665–7673
Publication Date (Web):July 28, 2010
https://doi.org/10.1021/bi100878q
Copyright © 2010 American Chemical Society
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    Abstract

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    The transport of lipids between membrane leaflets, also known as flip-flop, is a key process in regulating the lipid composition of biological membranes. It is also important for the growth of biogenic membranes that are the site for lipid synthesis. It has been shown that the mere presence of transmembrane α-helical peptides or proteins enhances the rate lipid flip-flop [Kol et al. (2001) Biochemistry 40, 10500−10506]. Using computational models of natural phospholipids with different headgroups, we calculated the free energy profiles for transferring single phospholipids from bulk water to the center of a dioleylphosphatidylcholine (DOPC) bilayer in the presence of transmembrane helices. The free energy barrier for phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) flip-flop decreased by a few kilojoules per mole when a WALP23 or KALP23 peptide was present in the membrane, while the barrier for PC was not affected. We observed large bilayer deformations during lipid flip-flop when the hydrophilic headgroup is in the hydrophobic interior of the bilayer. The presence of KALP23 or WALP23 decreased the size and stability of these defects, suggesting integral membrane proteins affect the mechanism of flip-flop. There was a large decrease in the free energy of desorption for PE and PG when transmembrane peptides were present. This suggests specific PE and PG interactions with the peptide have a large affect on their stability in the membrane, with implications on cellular lipid and protein trafficking.

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