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bioRxiv · 10.64898/2026.11.11.765848

Lipid Scrambling Amplifies Plasma Membrane Undulations via Anti-Registered Domains Stabilized by Long-Chain Sphingomyelin

Yamada, T.·Shinoda, W.
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Abstract

Lipid scrambling, which dissipates the transbilayer lipid asymmetry of plasma membranes (PMs), plays an essential role in various large-scale membrane remodeling processes. Although lipid domains have been implicated in these processes, the underlying mechanisms remain poorly understood, owing to the lack of a molecular-level picture of how lipid scrambling reorganizes these domains. Here, using coarse-grained molecular dynamics simulations of asymmetric and fully scrambled PM models, we show that lipid scrambling markedly enhances membrane undulations. We identify two key features of the domain organization underlying this enhancement in the scrambled PM: domain anti-registration, which couples to membrane curvature through a mismatch in preferred curvature between the two leaflets, and scrambling-induced domain enlargement, which permits this curvature to extend over large length scales. Simulations with different sphingomyelin (SM) compositions demonstrate that long-chain SMs stabilize anti-registered domains and the associated membrane curvature. Together, these results suggest a physical mechanism by which lipid scrambling primes the PM for remodeling through the reorganization of lipid domains, with long-chain SMs playing a key role. We also find that the interleaflet domain organization of the scrambled PM model depends strongly on system size, shifting from anti-registration to registration as the simulation box is reduced, and we discuss the origin of this finite-size effect.

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Yamada, T., Shinoda, W.. 2026-11-13. Lipid Scrambling Amplifies Plasma Membrane Undulations via Anti-Registered Domains Stabilized by Long-Chain Sphingomyelin. https://doi.org/10.64898/2026.11.11.765848

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