Presentation Information
[C11-03]The missing link between biomolecular condensates and functional amyloids
*Agur Sevink1, Art Hoti1, Jelger Risselada2 (1. Leiden University (Netherlands), 2. TU Dortmund (Germany))
Keywords:
proteins,biomolecular condensates,amyloids,cellular structures,molecular design
The discovery of membrane-less, phase-separated assemblies of proteins, nucleic acids, and carbohydrates in the form of dense liquid-like droplets, co-existing in the liquid environment of cells, has enriched our fundamental understanding of cellular spatio-temporal organization.[1] It has particularly shifted the traditional lipid-centric paradigm of biological compartmentalization towards a more multifaceted view. While the formation of biomolecular condensates (liquid-like droplets formed through liquid-liquid phase separation) or of functional amyloids (ordered solid-like fibrillar structures) by intrincically disordered peptides or proteins (IDPs) has commonly been interpreted as a proof that IDP assembly is limited to two key states, recent evidence suggests a much richer and functionally complex structural landscape. Notably, the discovery of LARKS (Low-Complexity Aromatic-Rich Kinked Segments),[2] which form dynamic hydrogels in isolation and drive the maturation of liquid condensates into gel-shell liquid-core architectures,[3] highlights the potential existence of intermediate assembly states.
Conducting inverse protein design, using genetic algorithms integrated with coarse-grained molecular dynamics simulations,[4] we demonstrate that IDPs can indeed behave as liquid crystals. Through a systematic exploration of sequence space, we investigated the molecular grammar governing the formation of IDP lyotropic liquid crystal phases. Our investigation reveals that these IDP phases closely parallel amphiphilic lipid assemblies, with sequence variations and environmental conditions mapping out a phase diagram that spans from planar membranes to curved structures such as micelles, worm-like micelles and vesicles. Significantly, our designed sequences exist near critical points, where subtle environmental changes or single amino acid substitutions modulate phase morphology. Overall, our findings provide a fundamental view into a hitherto unconsidered IDP assembly phase which has vast implications for both our fundamental understanding of cellular spatio-temporal organization, and the design of bio-compatible, protein based materials.
[1] Alberti, S., and Hyman, A.A. (2021). Nat. Rev. Mol. Cell Biol. 22, 196–213. https://doi.org/10.1038/s41580-020-00326-6.
[2] Kato, M. et al (2012), Cell 149, 753-767. doi: 10.1016/j.cell.2012.04.017.
[3] Blazques, S. et al (2023). cAdv Sci 10, 2207742. doi: 10.1002/advs.202207742.
[4] Methorst, J.; van Hilten, N.; Hoti, A.; Stroh, K.S. and H.J. Risselada. J. Chem. Theory Comput. 2024, 20, 5, 1763–1776. https://doi.org/10.1021/acs.jctc.3c00874.
Conducting inverse protein design, using genetic algorithms integrated with coarse-grained molecular dynamics simulations,[4] we demonstrate that IDPs can indeed behave as liquid crystals. Through a systematic exploration of sequence space, we investigated the molecular grammar governing the formation of IDP lyotropic liquid crystal phases. Our investigation reveals that these IDP phases closely parallel amphiphilic lipid assemblies, with sequence variations and environmental conditions mapping out a phase diagram that spans from planar membranes to curved structures such as micelles, worm-like micelles and vesicles. Significantly, our designed sequences exist near critical points, where subtle environmental changes or single amino acid substitutions modulate phase morphology. Overall, our findings provide a fundamental view into a hitherto unconsidered IDP assembly phase which has vast implications for both our fundamental understanding of cellular spatio-temporal organization, and the design of bio-compatible, protein based materials.
[1] Alberti, S., and Hyman, A.A. (2021). Nat. Rev. Mol. Cell Biol. 22, 196–213. https://doi.org/10.1038/s41580-020-00326-6.
[2] Kato, M. et al (2012), Cell 149, 753-767. doi: 10.1016/j.cell.2012.04.017.
[3] Blazques, S. et al (2023). cAdv Sci 10, 2207742. doi: 10.1002/advs.202207742.
[4] Methorst, J.; van Hilten, N.; Hoti, A.; Stroh, K.S. and H.J. Risselada. J. Chem. Theory Comput. 2024, 20, 5, 1763–1776. https://doi.org/10.1021/acs.jctc.3c00874.