Membrane hydrophobicity determines the activation free energy of passive lipid transport

Abstract

The collective behavior of lipids with diverse chemical and physical features determines a membrane's thermodynamic properties. Yet, the influence of lipid physicochemical properties on lipid dynamics, in particular interbilayer transport, remains underexplored. Here, we systematically investigate how the activation free energy of passive lipid transport depends on lipid chemistry and membrane phase. Through all-atom molecular dynamics simulations of 11 chemically distinct glycerophospholipids, we determine how lipid acyl chain length, unsaturation, and headgroup influence the free energy barriers for two elementary steps of lipid transport, lipid desorption, which is rate-limiting, and lipid insertion into a membrane. Consistent with previous experimental measurements, we find that lipids with longer, saturated acyl chains have increased activation free energies compared to lipids with shorter, unsaturated chains. Lipids with different headgroups exhibit a range of activation free energies; however, no clear trend based solely on chemical structure can be identified, mirroring difficulties in the interpretation of previous experimental results. Compared to liquid-crystalline phase membranes, gel phase membranes exhibit substantially increased free energy barriers. Overall, we find that the activation free energy depends on a lipid's local hydrophobic environment in a membrane and that the free energy barrier for lipid insertion depends on a membrane's interfacial hydrophobicity. Both of these properties can be altered through changes in lipid acyl chain length, lipid headgroup, and membrane phase. Thus, the rate of lipid transport can be tuned through subtle changes in local membrane composition and order, suggesting an unappreciated role for nanoscale membrane domains in regulating cellular lipid dynamics. SIGNIFICANCE Cell homeostasis requires spatiotemporal regulation of heterogeneous membrane compositions, in part, through non-vesicular transport of individual lipids between membranes. By systematically investigating how the chemical diversity present in glycerophospholipidomes and variations in membrane order influence the free energy barriers for passive lipid transport, we discover a correlation between the activation free energy and membrane hydrophobicity. By demonstrating how membrane hydrophobicity is modulated by local changes in membrane composition and order, we solidify the link between membrane physicochemical properties and lipid transport rates. Our results suggest that variations in cell membrane hydrophobicity may be exploited to direct non-vesicular lipid traffic.

Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid–membrane contacts

“…Consistent with this idea, we find that the hydrophobic tails of lipids in close proximity to both the apo and C1P-bound forms of CPTP are oriented more parallel to the membrane surface than expected for a POPC membrane without CPTP bound (Fig 5 Another membrane property that is especially key to lipid transport is the hydrophobicity of a lipid's local membrane environment. We previously demonstrated that the activation free energy for passive lipid transport correlates with the average number of hydrophobic contacts a lipid makes with surrounding membrane lipids, ⟨n CC ⟩ mem [26]. As ⟨n CC ⟩ mem decreases, the rate of passive lipid desorption from a membrane increases [26].…”

“…An additional puzzle is how CPTP overcomes the significant free energy barrier for lipid desorption from a membrane, which limits passive lipid transport rates [21][22][23][24][25]. We recently demonstrated that the activation free energy barrier for passive lipid desorption reflects the thermodynamic cost of breaking hydrophobic lipid-membrane contacts [25], and that it can be lowered by decreasing the hydrophobicity of the transferring lipid's local membrane environment [26]. Thus, we hypothesize that CPTP rapidly extracts C1P from a membrane by disrupting C1P-membrane hydrophobic contacts, thereby lowering the free energy barrier for lipid desorption and catalyzing C1P transport.…”

Construction of Bio‐inspired Film with Engineered Hydrophobicity to Boost Interfacial Reaction Kinetics of Aqueous Zinc–Ion Batteries

“…across the plasma membrane with moderate metabolic energy and fast migration speed. [30][31][32][33] Notably, the merits of high-efficiency ion transport and structural stability are the desired characteristics for AZIB cathode materials.…”

Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels

“…In lipid exchange mediated by “basket”-shaped LTPs that shuttle lipids back and forth by diffusion or tethered diffusion, the rate-limiting step for the transfer of a lipid from one membrane to another is the extraction or desorption from the membrane itself rather than the LTP-assisted transport ( Dittman and Menon, 2017 ; Wong et al, 2017 ). Spontaneous desorption of a lipid into the aqueous phase and henceforth between two membranes is energetically costly (∼10–20 kCal/mol) and extremely slow (several days) ( Rogers et al, 2021 ). Local membrane composition, lipid packing and membrane order also affects the energetics of lipid desorption ( Rogers et al, 2021 ).…”

“…Spontaneous desorption of a lipid into the aqueous phase and henceforth between two membranes is energetically costly (∼10–20 kCal/mol) and extremely slow (several days) ( Rogers et al, 2021 ). Local membrane composition, lipid packing and membrane order also affects the energetics of lipid desorption ( Rogers et al, 2021 ). LTPs lower the desorption energy barrier as they partition the lipid from a bilayer into a hydrophobic binding pocket instead of bulk aqueous solvent.…”