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Published on: January 7, 2020
Simulations of naïve and KLA-activated macrophage plasma membrane models
Yueqi Niu1, Si Jia Chen2, Jeffery B Klauda3
1Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD 20742, USA.
Abstract:
Macrophages (MAs), which play vital roles in human immune responses and lipid metabolisms, are implicated in the development and progression of atherosclerosis, a major contributor to cardiovascular diseases. Specifically, the abnormal lipid metabolism of oxidized low-density lipids (oxLDLs) in MAs is believed to be a crucial factor. However, the precise mechanism by which the MA membrane contributes to this altered lipid metabolism remains unclear. Lipidomic studies have revealed significant differences in membrane composition between various MA phenotypes. This study serves to provide and characterize complex realistic computational models for naïve (M0) and Kdo2-lipid A-activated (M1) state MA. Analyses of surface area per lipid (SA/lip), area compressibility modulus (KA), carbon‑hydrogen order parameter (SCH), electron density profile (EDP), tilt angles, two-dimension radial distribution functions (2D RDFs), mean squared displacement (MSD), hydrogen bonds (H-bonds), lipid clustering, and lipid wobble were conducted for both models. Results indicate that the M1 state MA membrane is more tightly packed, with increased chain order across lipid species, and forms PSM-DOPG-CHOL and PSM-SLPC-CHOL clusters. Importantly, the bilayer thicknesses reported for the models are in good agreement with experimental data for the thicknesses of transmembrane regions for MA integral proteins. These findings validate the described models as physiologically accurate for future computational studies of MA membranes and their residing proteins.
Insights
Computational models reveal distinct macrophage membrane properties. The M1 state macrophage membrane exhibits tighter packing and increased lipid chain order, offering insights into altered lipid metabolism in atherosclerosis.
Area of Science:
- Computational biophysics
- Cell membrane modeling
- Lipidomics
Background:
- Macrophages (MAs) are crucial in immune responses and lipid metabolism.
- Altered MA lipid metabolism, particularly of oxidized low-density lipids (oxLDLs), is linked to atherosclerosis.
- The role of MA membrane composition in altered lipid metabolism is not fully understood.
Purpose of the Study:
- To develop and characterize realistic computational models for naïve (M0) and Kdo2-lipid A-activated (M1) state macrophages.
- To investigate the biophysical properties of MA membranes in different activation states.
Main Methods:
- Creation of complex computational models for M0 and M1 state MA membranes.
- Analysis of membrane properties including surface area per lipid (SA/lip), area compressibility modulus (KA), order parameters (SCH), electron density profiles (EDP), tilt angles, radial distribution functions (2D RDFs), mean squared displacement (MSD), hydrogen bonds (H-bonds), lipid clustering, and lipid wobble.
- Validation of model bilayer thicknesses against experimental data for transmembrane protein regions.
Main Results:
- The M1 state MA membrane is characterized by tighter packing and increased lipid chain order compared to M0.
- Specific lipid clusters, including PSM-DOPG-CHOL and PSM-SLPC-CHOL, were identified in the M1 membrane.
- Computational model bilayer thicknesses align well with experimental measurements of MA integral protein transmembrane regions.
Conclusions:
- The developed computational models accurately represent physiological MA membranes.
- The findings provide a foundation for future computational studies on MA membrane function and protein interactions.
- The distinct membrane properties of M1 macrophages offer insights into their role in altered lipid metabolism and atherosclerosis.
