Lateral organization of complex lipid mixtures from multiscale modeling

Abstract

The organizational properties of complex lipid mixtures can give rise to functionally important structures in cell membranes. In model membranes, ternary lipid-cholesterol ͑CHOL͒ mixtures are often used as representative systems to investigate the formation and stabilization of localized structural domains ͑"rafts"͒. In this work, we describe a self-consistent mean-field model that builds on molecular dynamics simulations to incorporate multiple lipid components and to investigate the lateral organization of such mixtures. The model predictions reveal regions of bimodal order on ternary plots that are in good agreement with experiment. Specifically, we have applied the model to ternary mixtures composed of dioleoylphosphatidylcholine:18:0 sphingomyelin:CHOL. This work provides insight into the specific intermolecular interactions that drive the formation of localized domains in these mixtures. The model makes use of molecular dynamics simulations to extract interaction parameters and to provide chain configuration order parameter libraries.

Regulation of human EGF receptor by lipids

“…We produced the full-length human EGF receptor in ExpresSF+ insect cells and purified the receptor to high purity and homogeneity. We tested different lipid compositions and then focused our work on previously well-characterized ternary lipid mixtures of 1,2-dioleoylsn-glycero-3-phosphocholine, sphingomyelin (18∶0) and cholesterol in two different compositions (37.5∕37.5∕25 and 80∕15∕ 5 mol%), the former giving rise to two immiscible fluid membrane phases (ld∕lo), whereas the latter forms a single ld membrane phase (18,19). These two membrane systems could then be supplemented by the addition of gangliosides (0.5 mol%), which were reported previously to have effects on receptor activity (6).…”

Self-consistent mean-field model for palmitoyloleoylphosphatidylcholine–palmitoyl sphingomyelin–cholesterol lipid bilayers

“…In our SCMFT model [43,44,56,57], a three-dimensional lipid bilayer leaflet is cast as a two-dimensional field of weighted, chain-averaged order parameters: $$s\left(\overrightarrow{r}\right)=-\frac{n_{\text{tr}}}{n_s}\sum _{m=1}^{n_s}true(\frac{3}{2}{\text{cos}}^2{\beta }_m-\frac{1}{2}true)∕n_s,$$ where the weighting fraction $\frac{n_{tr}}{n_s}$ represents the fraction of dihedrals in a trans configuration ( n tr ) along a single chain to the number of dihedrals along that chain ( n s ); β m is the angle between the C-H bond vector and the bilayer normal for carbon m for the chain at the position $\overrightarrow{r}$. CHOL molecules are treated as two-dimensional “rods” that are free to diffuse through the order parameter field.…”

“…We show below that the effect of including orientational dependence is to slightly amplify the separation of lipids into regions rich in PSM separated from regions rich in POPC. Comparison with our SCMFT simulations of DOPC-SSM-CHOL [56] reveals that the degree of lateral organization in POPC-PSM-CHOL mixtures is reduced, and differences between order parameters in separated domains are more subtle. In Sec.…”

“…The model employs equilibrium statistical mechanical analysis to construct ternary diagrams with phase boundaries whose presence and location are modulated by interaction parameters. We recently published a model for ternary lipid mixtures that we applied specifically to DOPC– steroyl sphingomyelin (SSM)–CHOL bilayers [56]. The model projected three-dimensional lipid bilayer leaflets onto two-dimensional fields of chain order over which CHOL could diffuse.…”

“…In this paper we present a model of ternary-component lipid bilayers that builds on our previous modeling work [43,44,56,57] to include lipids with nonidentical chains. This model differs from other computational and theoretical models [52–55,58–65] in that it utilizes atomistic molecular dynamics (MD)-generated data as input to a SCMFT model that is used to characterize the structure and temporal evolution of ternary phase diagrams.…”