From lipid flip-flop to membrane nanopores and protein insertion

Gerhard Hummer

Max Planck Institute of Biophysics, Theoretical Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt am Main, Germany, Gerhard.Hummer@biophys.mpg.de

By combining molecular dynamics (MD) simulations with artificial intelligence (AI) tools, we overcome the inherent time scale limitations in studying biomolecular processes and extract mechanistic insights in real time. These AI-guided MD simulations allowed us to capture the assembly of transmembrane helices of an ER calcium sensor with atomic resolutions, identify the transition states of the assembly process, and link them to distinct assembly states. In addition, we could extensively sample exceedingly rare lipid flip-flop events across lipid bilayer leaflets. We identified multiple distinct mechanisms of lipid flip-flop, relating them to lipid type and membrane characteristics. Notably, the spontaneous formation of transient nanopores is of particular interest, as it facilitates the translocation of lipids with large polar headgroups, as well as other polar or charged molecules.  In connection with nanoporation, I will highlight our ongoing work on protein insertion.

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