Mots-Clés

molecular modeling structural bioinformatics aptamers algorithm

Description

DNA or RNA aptamers are single stranded oligonucleotides able to interact with high affinity and specificity to a molecular target. These molecular recognition abilities are due to the adoption of a specific 3D structure, which allows them to reach dissociation constants in the nano- to picomolar range.
This makes them exploitable for applications similar to those of antibodies and, thus, they have a strong therapeutic and diagnostic potential. The in vitro procedure to select apatmers is called SELEX and it consists in multiple selection and amplification rounds of a oligonucleotides fragments library incubated with the target. The procedure is long et has limits because of its strong dependence from the initial library. Bioinformatics and computational approaches can help in overcoming the SELEX limits and in rationalizing the selection of aptamers against a target of interest.

With this aim, we already developed AptaMat, an algorithm for the comparison of oligonucleotides secondary structures (doi: 10.1093/bioinformatics/btac752), and we have established a protocol for the prediction of the oligonucleotides 3D structures based on enhanced sampling molecular dynamics techniques.
The proposed PhD project is the direct continuation of this work:

• An in silico docking-based protocol for the prediction of the protein-aptamers complexes will be defined;
• Algorithms for the generation of oligonucleotides sequences folding in a desired secondary structure will be implemented in collaboration with the Laboratoire de Mathématiques Appliquées de Compiègne;
• A protocol for the in silico estimation of the affinity between the designed olignonucleotides and the target protein will be developed. The pipeline including all the different steps will be defined and tested on a system of interest (STAT5).