Post-Doctoral Research Visit F/M Combinatorial graph-based docking of pre-oriented RNA/DNA fragments on proteins

The CAPSID Inria team develops computational approaches for the modeling and docking of nucleic acids (NA = RNA/DNA) binding to proteins. While AI-based methods have revolutionized the modeling of protein complexes, its application to protein-NA complexes has provided mitigated success, and failed in the case of highly flexible single-stranded NA. We have developed a combinatorial approach to build atomic representations of single-stranded RNA bound to a protein [ORCA-3D project] [1]: RNA fragments are docked separately, then reassembled by path search in a graph of compatible poses. Our method is the only one to date capable of providing accurate structural models of ssRNA-protein complexes, using only protein structure and RNA sequence. 

[1] “Fragment-based modelling of single stranded RNA bound to RNA recognition motif containing proteins” Isaure Chauvot de Beauchêne, Sjoerd De Vries, Martin Zacharias. Nucleic Acids Research, 2016

“A hybrid combinatorial method for docking ssRNA on proteins at the thermodynamic equilibrium” , Chinmay Singhal, Yann Pony, Isaure Chauvot de Beauchene. RECOMB 2018

This post-doc aims at expanding the approach, with 3 main possible directions.

First, our method still generates too many decoys. We want to improve the sampling of models by a new docking approach, relying on stacking interactions between nucleotides and aromatic amino-acids. RNA/DNA fragments can be pre-oriented in stacking-compatible orientations, then an ultra-fast translation-based docking can be applied, for all possible stacking combinations. Very encouraging preliminary results have been obtained on the example of the hSSB1 ssDNA-binding protein implicated in cancers. We will compare the computational results with in vivo protein-ssDNA binding essays from our collaborators at the Queensland University of Technology (Brisbane, Australia).

Second, the current approach neglects the flexibility ofthe the protein. We will implement a multi-scale combinatorial way to represent protein conformational variability, to be integrated in the docking process. 

Third, the applicability could be extended to D/RNA made of both double-stranded and single-stranded regions We could use our home-made ProtNAff tool [2] to generate all 3D conformations of each sequence and structure type, and the new color-docking approach [3] (in collaboration with the AMIB team at the LIX lab) to assemble them.

[2] “ProtNAff: protein-bound Nucleic Acid filters and fragment libraries”. Moniot A, Guermeur Y, de Vries SJ, Chauvot de Beauchene I.. Bioinformatics 2022

[3] “Color Coding for the Fragment-Based Docking, Design and Equilibrium Statistics of Protein-Binding ssRNAs” Taher Yacoub, Roy Gonzalez-Aleman , Fabrice Leclerc, Isaure Chauvot de Beauchene, Yann Ponty. Recomb 2024

• Literature review of the relevant studies
• Implementation of new docking paradygms (Python)
  
• Design and execution of docking experiment on benchmarks
• Validation of the method and analyse of the results
• Writing dissertation, scientific articles and presenting the work in international conferences

Technical skills and level required :

• proficient in molecular modeling, especially molecular docking
• experience with DNA or RNA modeling
• experience in programming with Python

Languages :

• english C1

Relational skills :

• a biological background and/or experience in collaborating with biologists is a plus

Other valued appreciated :

• experience in working specifically on ssRNA/ssDNA-protein complexes

• Subsidized meals
• Partial reimbursement of public transport costs
• Leave: 7 weeks of annual leave + 10 extra days off due to RTT (statutory reduction in working hours) + possibility of exceptional leave (sick children, moving home, etc.)
• Possibility of teleworking (after 6 months of employment) and flexible organization of working hours
• Professional equipment available (videoconferencing, loan of computer equipment, etc.)
• Social, cultural and sports events and activities
• Access to vocational training
• Social security coverage

2788€ gross/month