Geissler, P. L. | Search bioRxiv

bioRxiv2021

Membrane Hydrophobicity Determines the Activation Free Energy of Passive Lipid Transport

The collective behavior of lipids with diverse chemical and physical features determines a membranes 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 glycerophos-pholipids, 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 lipids local hydrophobic environment in a membrane and that the free energy barrier for lipid insertion depends on a membranes 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. SIGNIFICANCECell 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.

biophysics↗

bioRxiv2020

Breakage of Hydrophobic Contacts Limits the Rate of Passive Lipid Exchange Between Membranes

The maintenance of heterogeneous lipid compositions among cellular membranes is key to biological function. Yet, even the simplest process that could be responsible for maintaining proper lipid distributions, passive lipid exchange of individual molecules between membranes, has eluded a detailed understanding, due in part to inconsistencies between experimental findings and molecular simulations. We resolve these discrepancies by discovering the reaction coordinate for passive lipid exchange, which enables a complete biophysical characterization of the rate limiting step for lipid exchange. Our approach to identify the reaction coordinate capitalizes on our ability to harvest over 1,000 unbiased trajectories of lipid insertion, an elementary step of passive lipid transport, using all-atom and coarse-grained molecular dynamics simulations. We find that the reaction coordinate measures the formation and breakage of hydrophobic contacts between the membrane and exchanging lipid. Consistent with experiments, free energy profiles as a function of our reaction coordinate exhibit a substantial barrier for insertion. In contrast, lipid insertion was predicted to be a barrier-less process by previous computational studies, which incorrectly presumed the reaction coordinate to be the displacement of the exchanging lipid from the membrane. Utilizing our newfound knowledge of the reaction coordinate, we formulate an expression for the lipid exchange rate to enable a quantitative comparison with experiments. Overall, our results indicate that the breakage of hydrophobic contacts is rate limiting for passive lipid exchange and provide a foundation to understand the catalytic function of lipid transfer proteins.

biophysics↗