CE45 - Interfaces: mathématiques, sciences du numérique –biologie, santé

Multiscale Exploration of RNA poLymorphism for drug desIgN – MERLIN

Submission summary

Non-coding RNA molecules make up for more than 90% of the genome of higher organisms and are known to be key elements in gene expression regulation in viruses. Targeting RNA with drugs would open to a whole new class of possible therapies, now mainly limited to proteins. However, the flexible and dynamic nature of RNAs, where multiple structures can be adopted by the same sequence, represents one of the main challenges associated with targeting them with small molecules. In this context, even when experimentally resolved 3D structures are available, modeling tools are needed to complete our understanding of the possible alternative configurations, how they can interconvert, and how the landscape is affected by external factors.
In this project we propose to develop a multiscale approach to the exploration of non-coding RNA energy landscapes to generate ensembles of structures for drug design and to investigate the formation of RNA/ligand complexes. Our approach will be based on path-sampling simulations using a combination of atomistic and coarse-grained models to ensure a large exploration of the energy landscape of the molecules. In order to make this process more efficient we will optimize our current RNA coarse-grained model using machine learning techniques. Once possible alternative conformations are unveiled, one needs to find binding pockets and propose RNA/ligand complexes. To this day research in this field is very limited. We therefore propose to develop tools for these tasks accounting for the specificity of RNA molecules.

Project coordination

Samuela Pasquali (Biologie Fonctionnelle et Adaptative)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LPENS Laboratoire de physique de l'ENS
BFA Biologie Fonctionnelle et Adaptative
LBT Laboratoire de Biochimie Théorique
CiTCoM UNIVERSITE PARIS CITE

Help of the ANR 629,800 euros
Beginning and duration of the scientific project: November 2022 - 48 Months

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