Société Française de Bioinformatique

Mots-Clés

condensates molecular modeling nucleic acids enhanced sampling molecular dynamics

Description

Multiscale computational investigation of PAR-seeded condensates in DNA damage response
Biomolecular condensates play a key role in the response to DNA damage by concentrating and organizing repair proteins at sites of DNA lesions. The formation of such condensates relies on the recognition of DNA damage by the PARP-1 enzyme, that then catalysis its (auto)Poly(ADP-ribose)-ylation (PARylation). PAR is an unstructured and highly charged nucleic acid that serves as a multivalent platform for non-covalent binding of proteins. These condensates selectively recruit and concentrate proteins involved in DNA damage repair, such as FUS (Fused in Sarcoma), p53 and EWS (Ewing Sarcoma), thus organizing the damage repair process. Accumulation of PAR and dysregulated PAR condensates have been linked to various diseases, including cancer and neurodegenerative disorders such as Alzheimer’s and Parkison’s diseases.
We propose in this M2 project to setup a multiscale simulation methodology to obtain a molecular understanding of the formation and properties of PAR-triggered condensates. The project will focus on the interaction between PAR and the FUS protein. Starting from coarse grain simulations of PAR-FUS condensates, our goal will be to setup and validate a protocol for all-atom MD simulations of these systems that will allow us to reveal the molecular level structure of these condensates and illuminate the factors modulating their properties. We will pay specific attention to 1) the choice of refined force fields (including benchamark of machine-learning potentials) to characterize PAR-FUS interactions in dilute solutions; 2) the setup of an adequate enhanced strategy techniques to sample such disordered systems ; 3) validation against experimental data obtained by our collaborators.

Techniques/Methods Molecular dynamics; Coarse-grain and all atom simulations ; Enhanced sampling ; programming for simulation analysis (Python).

Research environment The research will take place in the lab of Theoretical Biochemistry (LBT) with Élise Duboué Dijon (specilist of nucleic acid simulations at the all-atom scale) and Fabio Sterpone (modeling of condensate with coarse grained approaches). Our team is specialized in the simulation, at different scales, of biologically relevant processes. It is located in the very stimulating research environment of the Latin Quarter, at the heart of Paris.