Biophysical Society Conference | Estes Park 2023

Membrane Budding and Fusion

Poster Abstracts

36-POS Board 12 COMPUTATIONAL INSIGHTS INTO THE FUNCTIONING OF CAVEOLIN-1

Korbinian Liebl 1 ; Gregory Voth 1 ; 1 University of Chicago, Chicago, IL, USA

Caveolae are ~50-100 nm large invaginations in the plasma membranes acting as molecular sensors and protectors. Mature caveolae are built from 8S complexes that consist of Caveolin-1 (CAV1) proteins oligomerized into disk-like structures with a central beta-barrel. While these CAV1 oligomers are central to caveolae biogenesis and hence of high biological relevance, the underlying biophysics concerning membrane bending, cholesterol concentration and the role of posttranslational modifications is still elusive. We have addressed this lack of current understanding by performing Molecular Dynamics (MD) simulations with a system size of about 1 million atoms. Unrestrained microsecond-long simulations indicate only minor membrane bending exerted by the protein, but also can capture only modest lipid reorganization due to the relatively low timescale. To overcome this issue, we have also 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 central beta barrel of CAV1. Furthermore, the free energy profiles obtained from MetaDynamics simulations also reveal a clear enhancing effect of posttranslational modification toward cholesterol concentration. To ultimately understand caveolae formation, it is essential to understand the cooperative mechanistic interaction of several CAV1 oligomers. Since such simulations are computationally too expensive at the atomistic resolution, a coarse-grained representation is necessary. For this reason, we discuss the reliability of different coarse-grained approaches and give a detailed presentation of a bottom-up approach.

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