Cholesterol flip-flop: Insights from free energy simulation studies

  • Jo S
  • Rui H
  • Lim J
 et al. 
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The mechanism of lipid flip-flop motion is important for maintaining the asymmetric distribution of lipids in a biological membrane. To explore the energetics and mechanism of passive cholesterol flip-flop and its dependence on chain saturation, we performed two-dimensional umbrella sampling simulations in DPPC, POPC, and DAPC (dipalmitoyl-, palmitoyloleoyl-, and diarachidonylphosphatidylcholine) and used the string method to identify the most probable flip-flop paths based on the two-dimensional free energy maps. The resulting paths indicate that cholesterol prefers to tilt first and then move to the bilayer center where the free energy barrier exists. The barrier is lower in DAPC than in DPPC or POPC, and the calculated flip-flop rates show that cholesterol flip-flop in a poly-unsaturated bilayer is faster than in more saturated bilayers. The free energy barrier results from the unfavorable enthalpic contribution arising from cholesterol−water/lipid interactions and the favorable entropic contribution d...

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  • Sunhwan Jo

  • Huan Rui

  • Joseph B. Lim

  • Jeffery B. Klauda

  • Wonpil Im

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