Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction

Jeroen Methorst, Nino Verwei, Christian Hoffmann, Paweł Chodnicki, Roberto Sansevrino, Partha Pyne, Han Wang, Niek Hilten, Dennis Aschmann, Alexander Kros, Loren Andreas, Jacek Czub, Dragomir Milovanovic and Herre Jelger Risselada ()
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Jeroen Methorst: Leiden University
Nino Verwei: Leiden University
Christian Hoffmann: German Center for Neurodegenerative Diseases (DZNE)
Paweł Chodnicki: Gdańsk University of Technology
Roberto Sansevrino: German Center for Neurodegenerative Diseases (DZNE)
Partha Pyne: Max Planck Institute for Multidisciplinary Sciences
Han Wang: German Center for Neurodegenerative Diseases (DZNE)
Niek Hilten: Leiden University
Dennis Aschmann: Leiden University
Alexander Kros: Leiden University
Loren Andreas: Max Planck Institute for Multidisciplinary Sciences
Jacek Czub: Gdańsk University of Technology
Dragomir Milovanovic: German Center for Neurodegenerative Diseases (DZNE)
Herre Jelger Risselada: Leiden University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The existence of linear cholesterol-recognition motifs in transmembrane domains has long been debated. Evolutionary molecular dynamics (Evo-MD) simulations—genetic algorithms guided by (coarse-grained) molecular force-fields–reveal that thermodynamic optimal cholesterol attraction in isolated alpha-helical transmembrane domains occurs when multiple consecutive lysine/arginine residues flank a short hydrophobic segment. These findings are supported by atomistic simulations and solid-state NMR experiments. Our analyses illustrate that linear motifs in transmembrane domains exhibit weak binding affinity for cholesterol, characterized by sub-microsecond residence times, challenging the predictive value of linear CRAC/CARC motifs for cholesterol binding. Membrane protein database analyses suggest even weaker affinity for native linear motifs, whereas live cell assays demonstrate that optimizing cholesterol binding restricts transmembrane domains to the endoplasmic reticulum post-translationally. In summary, these findings contribute to our understanding of cholesterol-protein interactions and offer insight into the mechanisms of protein-mediated cholesterol regulation within membranes.

Date: 2025
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DOI: 10.1038/s41467-025-63769-5

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