Large phospholipid-number asymmetry is not required to reproduce plasma membrane physical properties

Authors

Popov, C. R., Trollmann, M. F., Zhang, C., Böckmann, R. A.

Abstract

Plasma membranes are compositionally asymmetric, but whether this lipid-type asymmetry is accompanied by a substantial phospholipid-number imbalance between leaflets remains debated. Here, we use microsecond all-atom molecular dynamics simulations to compare human red blood cell plasma membrane models with either strong phospholipid-number asymmetry and exoplasmic cholesterol enrichment or near-symmetric phospholipid and cholesterol numbers but preserved lipid-type asymmetry. Both asymmetric models reproduce a densely packed, ordered exoplasmic leaflet and a more fluid cytoplasmic leaflet. Strong phospholipid-number asymmetry, however, drives extensive cholesterol enrichment in the exoplasmic leaflet and amplifies membrane asymmetry, leading to large cholesterol-rich clusters, enhanced shallow hydrophobic exposure, reduced exoplasmic lipid mobility, lower ethanol permeability, and increased area compressibility. Comparison with available diffusion and alcohol-permeability measurements indicates that the strongly asymmetric model overestimates the immobilization and barrier properties of the exoplasmic leaflet, whereas the near-symmetric-number model better captures these dynamic observables. Our results suggest that lipid-type asymmetry is sufficient to reproduce many physical hallmarks of plasma membranes without requiring a large phospholipid-number imbalance.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Sep 2026.

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