Free energy profiles of lipid translocation across pure POPC and POPC/CHOL bilayer: all-atom molecular dynamics study

Abstract

All-atom molecular dynamics (MD) simulations of pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer and POPC bilayer containing cholesterol (POPC/CHOL) with CHARMM36 force field were carried out to investigate the effects of CHOL on structure and lipid translocation across the membranes. We calculated the potential mean force (PMF) profiles for translocation of POPC and CHOL along the pure POPC and the POPC/CHOL bilayer normal by umbrella sampling method. The obtained PMF profile of the POPC translocation was in good agreement with that of the previous MD study, showing that the estimated PMF profiles with the CHARMM36 force field should be reasonable. We found that the PMF peak appears slightly beyond the bilayer center. The CHOL effects on the PMF profile of POPC translocation were clearly observed; the free energy barrier for the flip-flop of lipid increased and, the energy for the desorption of lipid decreased. These changes in the PMF profile should be responsible for the tight packing of the POPC/CHOL bilayer. The PMF profiles for the CHOL translocation showed that the free energy barriers at the bilayer center were sufficiently smaller than those of POPC translocation, indicating that the CHOL can easily flip over compared to the POPC in the membrane. In the case of PMF of CHOL translocation in the POPC/CHOL system, while the PMF energy in the hydrophobic core region was higher than that of the pure POPC bilayer, the free energy difference at bilayer center was small.