Asymmetry and Heterogeneity in the Plasma Membrane
Teppei YAMADA *1, Wataru SHINODA2
1Graduate School of Environmental, Life, Natural Science and Technology, Okayama University
2Research Institute for Interdisciplinary Science, Okayama University
Plasma membranes (PMs) exhibit a pronounced asymmetry between their two leaflets in terms of phospholipid headgroup composition, degree of acyl chain unsaturation, and resulting membrane packing density. In addition to this interleaflet asymmetry, lateral heterogeneity—specifically, the formation of lipid domains—is another essential organizational feature of PMs with profound biological implications. However, the physical nature and even the existence of lipid domains in the individual leaflets of PMs remain poorly understood, limiting our comprehension of lipid asymmetry’s functional significance.
In this study, we elucidate the structure and dynamics of lipid domains in both leaflets of the PM using molecular dynamics (MD) simulations [1]. The lipid composition of our membrane model was based on recent lipidomic data on the human red blood cell PM [2]. Given that lipid domain formation typically occurs over time scales inaccessible to all-atom MD simulations, we utilized the coarse-grained SPICA force field [3], which enables accurate modeling of phase separation in multi-component lipid membranes. Here, we extended the lipid library of the SPICA to faithfully reflect the RBC PM lipidome.
To characterize lipid domain organization, we computed the two-dimensional distributions of the order parameter of phospholipid tails in each leaflet. Our analyses reveal that lipids in the outer (exoplasmic) leaflet are highly ordered and spatially homogeneous, whereas the inner (cytoplasmic) leaflet exhibits nanoscale (~10 nm) phase separation into coexisting ordered and disordered domains. Furthermore, lipid diffusion in the inner leaflet is approximately seven times faster than in the outer leaflet, giving rise to highly dynamic domain fusion and fission events.
These findings suggest distinct biophysical and functional roles for the two leaflets of the PM: the outer leaflet acts as a stable barrier to the extracellular environment, while the inner leaflet provides a dynamic platform for modulating protein localization and facilitating intracellular signaling.
[1] T. Yamada and W. Shinoda, Biophys. J., in press (2025). DOI: 10.1016/j.bpj.2025.06.026
[2] J.H. Lorent et al., Nat. Chem. Biol., 16, 644–652 (2020).
[3] S. Seo and W. Shinoda, J. Chem. Theory Comput., 15, 762–774 (2019).