Large phospholipid-number asymmetry is not required to reproduce plasma membrane physical properties
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.
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BibTeX
@misc{popov2026large,
title = {{Large phospholipid-number asymmetry is not required to reproduce plasma membrane physical properties}},
author = {C. R. Popov and M. F. Trollmann and C. Zhang and R. A. Böckmann},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749494},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749494v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Large phospholipid-number asymmetry is not required to reproduce plasma membrane physical properties
AU - C. R. Popov
AU - M. F. Trollmann
AU - C. Zhang
AU - R. A. Böckmann
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749494
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749494v1
AB - 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.
ER -