AI-based cryo-EM approach to develop and evaluate small proteins to regulate the master regulator of cellular homeostasis (joint PhD with the University of Melbourne)

This project focuses on VCP/p97, a key protein that acts as a master regulator of cellular homeostasis by extracting and unfolding damaged or unwanted proteins for processing and removal [1]. Defects in VCP/p97 function are linked to several neurodegenerative and muscle diseases, while in cancer cells VCP/p97 activity is often exploited to cope with the unusually high burden of misfolded and abnormal proteins. VCP/p97 is also hijacked by many viruses to support key stages of viral infection, including entry, replication, and manipulation of host cell pathways.

In this project, a PhD student will apply AI‑based protein design approaches and leverage advanced computational tools to design small, custom‑made protein binders that can attach to VCP/p97 and alter its conformational dynamics and molecular function. The project will build on the MDSPACE image analysis software [2], and its application to characterising VCP/p97 dynamics [3], to analyse cryo‑electron microscopy (cryo-EM) datasets of VCP/p97 and VCP/97–ligand complexes. This will enable obtaining detailed maps of conformational states associated with mini-protein engagement, allowing assessment of how designed binders control VCP/p97 conformational dynamics. By combining computational protein design with biochemical experiments and high‑resolution cryo-EM, the project aims to reveal how these binders reshape the structure and behaviour of VCP/p97. This work will improve our understanding of how essential protein machines are regulated in cells and may help inform future strategies for selectively targeting proteostasis pathways in neurodegenerative disease, cancer, and viral infection.

[1] Valimehr, S., et al., Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases. Biomolecules, 2023. 13(5).https://www.mdpi.com/2218-273X/13/5/737

[2] Vuillemot, R., et al., MDSPACE: Extracting Continuous Conformational Landscapes from Cryo-EM Single Particle Datasets Using 3D-to-2D Flexible Fitting based on Molecular Dynamics Simulation. J Mol Biol, 2023. 435(9): p. 167951.https://hal.science/hal-03929029

[3] Valimehr, S., et al., Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes. Int J Mol Sci, 2024. 25(6). https://hal.science/hal-04519643

The PhD student will be co-supervised by a researcher from University of Melbourne (for AI-based protein design, protein expression and purification, biochemical characterisation, and cryo-electron microscopy data collection) and a researcher from Sorbonne University (regarding data analysis using novel computational methods). This is a joint PhD thesis between Sorbonne University and the University of Melbourne, with a minimum two year stay at the University of Melbourne and a mandatory one year stay (during the second year of the PhD) at Sorbonne University. At the University of Melbourne, the student will join the Cryo-EM Laboratory for Studies of Molecular Machines in the Department of Biochemistry and Pharmacology located in the Bio21 Molecular Science & Biotechnology Institute. At Sorbonne University, the student will join the IMPMC-UMR 7590 laboratory (https://impmc.sorbonne-universite.fr/en).

As this is a joint PhD program between Sorbonne University and the University of Melbourne, candidates must meet the doctoral admission requirements of both universities. For international applicants to the University of Melbourne, this generally corresponds to a very high academic level (often around 80% of the maximum grade, or equivalent depending on the grading system). In the French system, this generally corresponds to an excellent Master 2 performance, ranking among the top 10% of the class.

Candidate profile :

Academic background

• Strong background in structural biology, biophysics, computational biology, or a closely related discipline.

Technical experience

• Existing familiarity with at least one of the following areas:
  • Structural biology and/or cryo‑electron microscopy (cryo‑EM)
  • Computational protein modelling and design
  • Protein biochemistry and biophysics
• Interest in and capacity for development of bioinformatics methods and programming in Python

Academic Eligibility

• Applicants must meet the PhD admission requirements of both universities: the University of Melbourne and Sorbonne University. University of Melbourne entry requirements: First Class Honours (H1) or equivalent (~80%; excellent Master 2, top 10%), and English language requirements.