Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Poster Abstracts

17-POS Board 5 MULTISCALE-SIMULATIONS OF MEMBRANE-REMODELING BY CAVEOLIN-1 Korbinian Liebl ; Gregory A Voth 1 ; 1 University of Chicago, Chicago, IL, USA Caveolae are ~50-100 nm large invaginations in the plasma membrane, initiating the formation of endocytic vesicles. Mature caveolae are built from 8S complexes that consist of Caveolin-1 (CAV1) protomers oligomerized into disk-like structures with a central beta-barrel. Intriguingly, the CAV1-8S complexes accumulate cholesterol and are embedded in only one lipid layer, leaving the beta-barrel exposed to solvent. However, how this molecular architecture orchestrates the intricate molecular functions that are central to caveolae biogenesis is not understood. In addition, also the role of posttranslational modifications (palmitoylation) of the CAV1 monomers has remained elusive. To gain better understanding of the molecular functioning of the CAV1-8S complexes, we have performed extensive atomistic Molecular Dynamics (MD) simulations. Unbiased microsecond-long simulations of a CAV1-8S complex indicate only minor membrane-bending due to the protein complex. To overcome the modest lipid reorganization on this timescale, we have performed comparative MetaDynamics simulations that greatly enhance the sampling of lipid conformations. In this way, we have been able to monitor the concentration of cholesterol within the beta barrel of the CAV1-8S complex. Furthermore, the obtained free energy profiles reveal that posttranslational modifications reinforce accumulation of cholesterol. Nevertheless, the atomistic simulations are not sufficient to explain how CAV1-8S complexes organize a flat-to-curved transition of the lipid bilayer to form endocytic vesicles. Thus, we have built a rigorous bottom-up coarse-grained model that enables accurate simulations of multiple membrane embedded CAV1-8S complexes. Based on these cutting-edge simulations, we give new insight into caveolae formation by showing how CAV1-8S complexes cooperatively leverage membrane bending. We also discuss the impact of electrostatic repulsion between distinct complexes and bring to light the importance of cholesterol concentration. Finally, we emphasize that our approach extends the state-of the art of protein-lipid coarse-graining and paves the way for accurate coarse-grained models on length scales up to ~1 µm.

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