Mots-Clés

Glycosylation Antibody

Description

Context and project objectives.

More than 80% of membrane proteins are extensively modified by complex sugars – glycans - that are covalently attached to proteins during their synthesis. Despite a general awareness that N-glycans are very diverse and may strongly impact protein accessibility and function in health and disease, we know very little on their impact on protein structure, hindering structure-function studies.
Deep learning approaches now enable de novo design of small binders and nanobodies for tailored tuning of protein exposure and activity. These approaches are particularly relevant for neurotransmitter receptors (NTRs), opening promising perspectives to understand and correct the unwanted action of auto-immune antibodies naturally occurring in the brain and responsible for severe pathologies. Glycans are, however, typically ignored in this context, potentially explaining why only a small proportion of AI-designed binders efficiently bind to their cognate proteins in a physiological context.
In collaboration with biophysicists of the Malopolska Center of Biotechnology in Krakow and the Physico-Chemical Biology Institute (IBPC) in Paris, we are developing novel computational approaches to generate realistic atomistic models of complete glycosylated neurotransmitter receptors (NTRs). Our current work shows that such models significantly improve predictions of NTR interactions with AI-designed nanobodies and receptor targeting by auto-immune antibodies found in patients. Expending on this work, we are seeking to perform state-of-the-art molecular dynamics simulations and co-folding experiments to deepen and generalize these findings.

Financial support (Paris).

Genci/Idris for High-Performance Computing, INSERM (IRP 2025-2029) and the French National Research Agency (ANR 2025-2029, 2026-2030). Funds are available to support visits and joint meetings with the Sikora lab in Krakow.

Dates and candidate profile.

The ideal candidate will have strong coding skills in Python, a keen interest in computational structural biology, biophysics and molecular dynamics, be self-motivated and have the ability to work collaboratively in a team.
M2 internships will be housed at the Institute for Psychiatry and Neurosciences of Paris (IPNP) and will be co-supervised by Cyril Hanus (IPNP) and Antoine Taly (IBPC). M2 Internships will be possible from January to July 2026. M2 candidates interested in pursuing a PhD will be encouraged to apply for competitive PhD funding in June.

Participating labs/principal investigators

Dr. Cyril Hanus, Dynamics of Neuronal Structures (dir. Zolt Lenkei), IPNP, Paris. INSERM – Paris Cité University / Dr. Antoine Taly, Laboratory of Theorical Biochemistry (dir. Marc Baaden), IBPC, Paris. CNRS – Paris Cité University / Dr. Mateusz Sikora. Dioscuri Centre Malopolska Centre of Biotechnology (MCB) | Jagiellonian Universit /Krakow.

Relevant papers from participating teams:

J. Chem Theory Comput. 2024 Nov 26;20(22):10259-10265. doi: 10.1021/acs.jctc.4c01092; Cell. 2024 Feb 29;187(5):1296-1311.e26. doi:
10.1016/ j.cell.2024.01.034