Push and Pull Forces in Lipid Raft Formation: The Push Can Be as Important as the Pull

Abstract

Nearest-neighbor recognition measurements have been made using exchangeable mimics of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine in the liquid-ordered (lo) and liquid-disordered (ld) states. In the ld phase, the net interaction between these two lipids is repulsive. In the lo phase, their interactions are neither attractive nor repulsive. These results, together with previous nearest-neighbor measurements, imply that the overall driving force for lipid domain formation in bilayers composed of high-melting lipids, low-melting lipids, and cholesterol, corresponds to a strong pull (attraction) between the high-melting lipids and cholesterol, a significant push (repulsion) between the low-melting and high-melting lipids, and a significant push between the low-melting lipids and cholesterol. In a broader context, these results provide strong support for the notion that repulsive forces play a major role in the formation of lipid rafts.

Pair interactions among ternary DPPC/POPC/cholesterol mixtures in liquid-ordered and liquid-disordered phases

“…The highest profile is DPPC-POPC in the l d phase, suggesting that interactions between saturated phospholipids and monounsaturated phospholipids in the l d phase are most unfavorable, which is consistent with the push force measured by Regen et al 8 The resulting PMF for the pairs involving cholesterol are shown in Figure 3b. In 6 Å < r < 10 Å, there is a clear minimum for CHOL-DPPC in the l o phase compared to the other cholesterollipid interactions, which corresponds to the strong pull proposed by Regen et al 8 The interactions for CHOL-POPC in either the l d phase or the l o phase are clearly unfavorable with respect to the strong pull of CHOL-DPPC in the l o phase, which can be attributed to the significant push between cholesterol and monounsaturated phospholipids 3,8 . In contract to the other interactions, the PMF for CHOL-CHOL has several local minima keeping the same positions in the l d phase and the l o phase, which indicates that the favorable packing distances among cholesterol are not affected by the phases.…”

“…AA, BB, and AB. The mutual interactions between lipids A and B in equilibrium can be characterised by an effective association constant, K, defined by Finally, for the case of CHOL-POPC interactions, we also obtain a good qualitative agreement with experiments in the l o phase, whereas in the l d phase the simulation result of K = 6.2 is not in agreement with experiment, which reveals a repulsive interaction 8 . The difference with experiment could be due to the difference in composition of the membrane used in the simulations, which could alter the subtle balance between push and pull forces which define lipid pairings.…”

“…They showed that DPPC and cholesterol exhibit strong attraction 3,7 . More recently, they measured the interactions between DPPC and POPC and found that such interactions are significantly repulsive in the l d phase but are neither attractive nor repulsive in the l o phase 8 .…”

Domain Stability in Biomimetic Membranes Driven by Lipid Polyunsaturation

“…Exclusion of cholesterol from the disordered domain leads to its concentration in the DPPC-rich domains, enhancing its ordering effect on DPPC. This interpretation is similar to the “push-pull” mechanism for ordered domain formation, based on measurements of pairwise interaction parameters between lipids 85–86 and NMR experiments 48, 87 . Together, these effects enhance the difference between ordered and disordered lipids, which ultimately promotes their separation into stable domains.…”

Lipid Raft Formation: Key Role of Polyunsaturated Phospholipids

“…[23][24][25][26] As discussed elsewhere,w hat distinguishes this technique from virtually all other methods that have been used to study nearest-neighbor interactions is its directness and its extreme sensitivity;i .e., it can detect changes in free energies of interaction down to tens of calories per mole-a magnitude that is sufficient to significantly affect the lateral organization of membranes. [23][24][25][26] As discussed elsewhere,w hat distinguishes this technique from virtually all other methods that have been used to study nearest-neighbor interactions is its directness and its extreme sensitivity;i .e., it can detect changes in free energies of interaction down to tens of calories per mole-a magnitude that is sufficient to significantly affect the lateral organization of membranes.…”