Models for randomly distributed nanoscopic domains on spherical vesicles

Abstract

The existence of lipid domains in the plasma membrane of biological systems has proven controversial, primarily due to their nanoscopic size-a length scale difficult to interrogate with most commonly used experimental techniques. Scattering techniques have recently proven capable of studying nanoscopic lipid domains populating spherical vesicles. However, the development of analytical methods able of predicting and analyzing domain pair correlations from such experiments has not kept pace. Here, we developed models for the random distribution of monodisperse, circular nanoscopic domains averaged on the surface of a spherical vesicle. Specifically, the models take into account (i) intradomain correlations corresponding to form factors and interdomain correlations corresponding to pair distribution functions, and (ii) the analytical computation of interdomain correlations for cases of two and three domains on a spherical vesicle. In the case of more than three domains, these correlations are treated either by Monte Carlo simulations or by spherical analogs of the Ornstein-Zernike and Percus-Yevick (PY) equations. Importantly, the spherical analog of the PY equation works best in the case of nanoscopic size domains, a length scale that is mostly inaccessible by experimental approaches such as, for example, fluorescent techniques and optical microscopies. The analytical form factors and structure factors of nanoscopic domains populating a spherical vesicle provide a new and important framework for the quantitative analysis of experimental data from commonly studied phase-separated vesicles used in a wide range of biophysical studies.

Deciphering Melatonin-Stabilized Phase Separation in Phospholipid Bilayers

“…It can be written as where the averages ⟨···⟩ are ensemble averages over many vesicles, which can vary in size (i.e., polydisperse). The form factor is given by where ρ s is the scattering length density, SLD, of the solvent and ρ­( r ) is the vesicle SLD. , For a dilute solution of vesicles (i.e., 10–20 mg/mL) used for experimentation, we can approximate S ( q ) ≈ 1 by ignoring vesicle–vesicle interactions that contribute to the scattering. Thus, we are only concerned with the spherically averaged intensity, I ( q ), that depends on the magnitude of the wave vector, q = | q |, which is related to the neutron wavelength, λ n , and the scattering angle, θ, according to q = (4π/λ n )­sin­(θ/2), the scattered intensity is an orientationally averaged cross section.…”

“…This approach is based on general symmetry principles and is able to address different phase-separated states . Unlike previous SANS analyses that assume a particular geometry for the separated phases, such as a single disc-like domain or an assortment of circular domains on the vesicle surface, , our model is based on the most probable thermodynamic state of the membrane and does not assume any specific domain geometry. This so-called Landau–Brazovskii approach for interpreting scattering data from laterally heterogeneous lipid vesicles, may be applicable in identifying many different domain configurations, including patterned membranes and disordered phases with transient structures …”

DOPC versus DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA

“…Regardless of the fact that our membranes were very simple they still give the information about certain domains formed in the shell of complex LNPs. 11,84 Taking into consideration the structural information obtained from computed properties one can conclude that the amine lipid forms aggregates in DOPC lipid bilayers at a concentration of 15 mol% of DLin-MC3-DMA, while at the same concentration in DOPE the structures create hydrophobic nets on the surface of the membrane: between the phosphate and carbonyl groups of DOPE. These nets are in the case of our simulations seen as causes of a slow lateral diffusion at higher concentrations of the amine lipid and the pore formation in the DOPE membrane with the lowest content of DLin-MC3-DMA, probably, due to the proton transfer disruption around the phospholipid headgroups.…”

“…The obstacle here is the polydispersity of therapeutics, which can be seen in the variety of sizes of LNPs 10 in the same mixture and in the diversity of textures within a single particle. 11 Typically, the experimental studies have to be combined with structural modelling, 12,13 despite the computational limits, in order to refine the texture of the LNPs on an atomistic level and reveal the exact mechanisms behind the pharmacological properties of therapeutics.…”

Lateral heterogeneity and domain formation in cellular membranes

“…The structure factor, S ( q ), for the lipid membrane can be measured via a scattering (neutron or X-ray) experiment( Anghel et al, 2018 ). Small angle neutron scattering is particularly valuable as it provides better contrast to probe the lateral membrane heterogeneity, even when these heterogeneities are nanoscopic ( Pan et al, 2013 , Anghel et al, 2019 ).…”