Abstract
Interest in lipid interactions with proteins and other biomolecules is emerging not only in fundamental biochemistry but also in the field of nanobiotechnology where lipids are commonly used, for example, in carriers of mRNA vaccines. The outward-facing components of cellular membranes and lipid nanoparticles, the lipid headgroups, regulate membrane interactions with approaching substances, such as proteins, drugs, RNA, or viruses. Because lipid headgroup conformational ensembles have not been experimentally determined in physiologically relevant conditions, an essential question about their interactions with other biomolecules remains unanswered: Do headgroups exchange between a few rigid structures, or fluctuate freely across a practically continuous spectrum of conformations? Here, we combine solid-state NMR experiments and molecular dynamics simulations from the NMRlipids Project to resolve the conformational ensembles of headgroups of four key lipid types in various biologically relevant conditions. We find that lipid headgroups sample a wide range of overlapping conformations in both neutral and charged cellular membranes, and that differences in the headgroup chemistry manifest only in probability distributions of conformations. Furthermore, the analysis of 894 protein-bound lipid structures from the Protein Data Bank suggests that lipids can bind to proteins in a wide range of conformations, which are not limited by the headgroup chemistry. We propose that lipids can select a suitable headgroup conformation from the wide range available to them to fit the various binding sites in proteins. The proposed inverse conformational selection model will extend also to lipid binding to targets other than proteins, such as drugs, RNA, and viruses.
Highlights
IntroductionChemical compositions of lipid headgroups vary between different organelles and organisms, and specific interactions with certain lipid headgroups are known to be essential for the function of several proteins.[1,5] the driving forces for specific interactions between lipids and membrane-binding substances are not fully understood because conformational ensembles of lipids in the physiologically relevant liquid state have not been experimentally determined
The most accurate experimental information on conformational ensembles of lipids in this biologically relevant phase is typically derived from NMR experiments, from the C−H bond order parameters, SCH = 1/2 ⟨3 cos[2] θ − 1⟩, where θ is the angle between the C−H bond and membrane normal, and the average is taken over the conformational ensemble of lipids.[14−16] Because these order parameters are similar to those in living cells,[17−19] the model membranes can be used to resolve the lipid headgroup conformations in biological conditions
C−H bond order parameters SCH from NMR experiments suggest that lipid headgroup conformational ensembles depend on lipid type (PC, PE, PG, or PS) and membrane charge
Summary
Chemical compositions of lipid headgroups vary between different organelles and organisms, and specific interactions with certain lipid headgroups are known to be essential for the function of several proteins.[1,5] the driving forces for specific interactions between lipids and membrane-binding substances are not fully understood because conformational ensembles of lipids in the physiologically relevant liquid state have not been experimentally determined. It is not clear if the specificity arises from the differences in accessible conformations between lipid types or from specific intermolecular lipid−protein interactions.
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