Přehled
Doctoral study program: Life Sciences
Supervisor: prof. RNDr. Robert Vácha, PhD.
Topic title : Overcoming the Endosomal Barrier: Design Principles of Fusogenic Proteins for Lipid Vesicles
Annotation:
Cancer remains one of the leading causes of mortality worldwide, claiming nearly ten million lives each year. One promising treatment is cancer immunotherapy using mRNA encapsulated in lipid vesicles, which facilitate efficient drug transport into target cells. However, the delivery of mRNA into the cell remains a challenge due to limited endosomal escape. To overcome the endosomal escape barrier, this project aims to computationally design proteins that induce fusion between lipid vesicles and endosomes. Using mesoscopic simulations, we will identify the key structural features of proteins with a transmembrane domain that promote membrane fusion. These insights will inform the rational design of coiled-coil peptide sequences with said features and assess their capacity to induce membrane fusion using Martini coarse-grained simulations. This research will elucidate the molecular mechanism of protein-mediated membrane fusion, establishing a framework for the rational design of fusogenic proteins. The designed proteins will enable the development of lipid vesicles with increased endosomal escape efficiency, which has the potential to improve the intracellular delivery of mRNA. Collectively, these advances will contribute to the broader vision of developing clinically relevant platforms that expand the therapeutic potential of nucleic acid medicines and accelerate their translation into effective therapies.
Recommended literature:
Blasco S.; Sukeník, L.; Vácha, R.: Nanoparticle induced fusion of lipid membranes. Nanoscale 2024, 16, 10221-10229, doi: 10.1039/D4NR00591K
Risselada H.J.; Bubnis G.; Grubmüller H.: Expansion of the fusion stalk and its implication for biological membrane fusion. Proc. Natl. Acad. Sci. USA 2014, 111, 30, 11043-11048, doi: 10.1073/pnas.1323221111
Jahn R.; Cafiso D.C.; Tamm L.K.: Mechanisms of SNARE proteins in membrane fusion. Nat. Rev. Mol. Cell. Bio.l 2024, 25, 101–118, doi: 10.1038/s41580-023-00668-x
Wang L.; Wang G.; Mao W.; et al. Bioinspired engineering of fusogen and targeting moiety equipped nanovesicles. Nat Commun 2023, 14, 3366, doi: 10.1038/s41467-023-39181-2
Research area:
Computational biophysics, drug delivery, protein design
Keywords:
Computer simulations, coarse-grained model, molecular dynamics, membrane fusion, fusion protein, protein design
Funding of the PhD candidate:
ERC, GACR grants
In the academic year 2026/27 the net income of the CEITEC PhD School student is expected to be at least CZK 29,400 (approx. EUR 1215)
Requirements for candidate:
• MSc in computational biophysics/chemistry/physics and related fields
• Experience with Molecular Dynamics using coarse grained or atomistic models
• Advantage is experience with simulations of disordered proteins/polymers and membranes
• Excellent track record
• Good English language – spoken and written
• Motivated person with collaborative mind set
Information about the supervisor:
Current group: 9 postdocs, 3 PhD students,2 Master students, 4 technicians
Current projects are:
National Institute of Virology and Bacteriology, ERC consolidator grant, ERC proof of concept grant, Czech Science Foundation grant, TACR Proof of Concept, INTER-COST
In total 84 publications with more than 4700 citations (WoS) and H-index 37.
Start date: September 2026
Sign-up link: https://www.ceitec.eu/overcoming-the-endosomal-barrier-design-principles-of-fusogenic-proteins-for-lipid-vesicles/t11640
