skip to main content

Search for: All records

Award ID contains: 1817929

Note: When clicking on a Digital Object Identifier (DOI) number, you will be taken to an external site maintained by the publisher. Some full text articles may not yet be available without a charge during the embargo (administrative interval).
What is a DOI Number?

Some links on this page may take you to non-federal websites. Their policies may differ from this site.

  1. Abstract

    We studied the transleaflet coupling of compositionally asymmetric liposomes in the fluid phase. The vesicles were produced by cyclodextrin-mediated lipid exchange and contained dipalmitoyl phosphatidylcholine (DPPC) in the inner leaflet and different mixed-chain phosphatidylcholines (PCs) as well as milk sphingomyelin (MSM) in the outer leaflet. In order to jointly analyze the obtained small-angle neutron and X-ray scattering data, we adapted existing models of trans-bilayer structures to measure the overlap of the hydrocarbon chain termini by exploiting the contrast of the terminal methyl ends in X-ray scattering. In all studied systems, the bilayer-asymmetry has large effects on the lipid packing density. Fully saturated mixed-chain PCs interdigitate into the DPPC-containing leaflet and evoke disorder in one or both leaflets. The long saturated acyl chains of MSM penetrate even deeper into the opposing leaflet, which in turn has an ordering effect on the whole bilayer. These results are qualitatively understood in terms of a balance of entropic repulsion of fluctuating hydrocarbon chain termini and van der Waals forces, which is modulated by the interdigitation depth. Monounsaturated PCs in the outer leaflet also induce disorder in DPPC despite vestigial or even absent interdigitation. Instead, the transleaflet coupling appears to emerge here from a matching of the inner leaflet lipids to the larger lateral lipid area of the outer leaflet lipids.

    Graphical abstract

    more » « less
  2. The compositional asymmetry of biological membranes has attracted significant attention over the last decade. Harboring more differences from symmetric membranes than previously appreciated, asymmetric bilayers have proven quite challenging to study with familiar concepts and techniques, leaving many unanswered questions about the reach of the asymmetry effects. One particular area of active research is the computational investigation of composition- and number-asymmetric lipid bilayers with molecular dynamics (MD) simulations. Offering a high level of detail into the organization and properties of the simulated systems, MD has emerged as an indispensable tool in the study of membrane asymmetry. However, the realization that results depend heavily on the protocol used for constructing the asymmetric bilayer models has sparked an ongoing debate about how to choose the most appropriate approach. Here we discuss the underlying source of the discrepant results and review the existing methods for creating asymmetric bilayers for MD simulations. Considering the available data, we argue that each method is well suited for specific applications and hence there is no single best approach. Instead, the choice of a construction protocol—and consequently, its perceived accuracy—must be based primarily on the scientific question that the simulations are designed to address.

    more » « less
    Free, publicly-accessible full text available July 1, 2024
  3. The development of electron cryomicroscopy (cryo-EM) has evolved immensely in the last several decades and is now well-established in the analysis of protein structure both in isolation and in their cellular context. This review focuses on the history and application of cryo-EM to the analysis of membrane architecture. Parallels between the levels of organization of protein structure are useful in organizing the discussion of the unique parameters that influence membrane structure and function. Importantly, the timescales of lipid motion in bilayers with respect to the timescales of sample vitrification is discussed and reveals what types of membrane structure can be reliably extracted in cryo-EM images of vitrified samples. Appreciating these limitations, a review of the application of cryo-EM to examine the lateral organization of ordered and disordered domains in reconstituted and biologically derived membranes is provided. Finally, a brief outlook for further development and application of cryo-EM to the analysis of membrane architecture is provided. 
    more » « less
  4. null (Ed.)
    It is well known that the lipid distribution in the bilayer leaflets of mammalian plasma membranes (PMs) is not symmetric. Despite this, model membrane studies have largely relied on chemically symmetric model membranes for the study of lipid–lipid and lipid–protein interactions. This is primarily due to the difficulty in preparing stable, asymmetric model membranes that are amenable to biophysical studies. However, in the last 20 years, efforts have been made in producing more biologically faithful model membranes. Here, we review several recently developed experimental and computational techniques for the robust generation of asymmetric model membranes and highlight a new and particularly promising technique to study membrane asymmetry. 
    more » « less
  5. null (Ed.)
    We addressed the frequent occurrence of mixed-chain lipids in biological membranes and their impact on membrane structure by studying several chain-asymmetric phosphatidylcholines and the highly asymmetric milk sphingomyelin. Specifically, we report trans-membrane structures of the corresponding fluid lamellar phases using small-angle X-ray and neutron scattering, which were jointly analyzed in terms of a membrane composition-specific model, including a headgroup hydration shell. Focusing on terminal methyl groups at the bilayer center, we found a linear relation between hydrocarbon chain length mismatch and the methyl-overlap for phosphatidylcholines, and a non-negligible impact of the glycerol backbone-tilting, letting the sn1-chain penetrate deeper into the opposing leaflet by half a CH2 group. That is, penetration-depth differences due to the ester-linked hydrocarbons at the glycerol backbone, previously reported for gel phase structures, also extend to the more relevant physiological fluid phase, but are significantly reduced. Moreover, milk sphingomyelin was found to follow the same linear relationship suggesting a similar tilt of the sphingosine backbone. Complementarily performed molecular dynamics simulations revealed that there is always a part of the lipid tails bending back, even if there is a high interdigitation with the opposing chains. The extent of this back-bending was similar to that in chain symmetric bilayers. For both cases of adaptation to chain length mismatch, chain-asymmetry has a large impact on hydrocarbon chain ordering, inducing disorder in the longer of the two hydrocarbons. 
    more » « less
  6. null (Ed.)