TORBEEV Vladimir

Combinatorial chemical synthesis of conformationally constrained analogs of intrinsically disordered proteins to dissect complex protein-protein interaction networks and to develop novel drug discovery strategies

 

This proposal aims at developing experimental methodologies for high-throughput total chemical synthesis of proteins using microfluidic reactors and application of new methods for combinatorial synthesis of libraries of conformationally-constrained analogs (CCAs) of intrinsically disordered proteins (IDPs).

Conformational constrains will be realized by installing α-methyl groups at selected sited to enhance residual α-helical structures. The sites for α-methyl substitution will be selected based on bioinformatic algorithms, specifically designed for IDPs, which annotate protein sequences with their putative secondary structures and probabilities to bind a protein interaction partner. The libraries of CCAs will be screened to identify protein interaction partners, enabling dissecting of the role of various IDP conformers in protein-protein interaction networks, understanding the cross-talk between proteins (transfer of information) and validating self-organization mechanisms of networks in response to stimuli.

Furthermore, the CCAs libraries will facilitate identification of peptide / small-molecule effectors (e.g. inhibitors, agonists) of protein-protein interactions of interest by using conformationally-defined, yet functional IDP analogs for compound screening. In summary, this proposal outlines a unique strategy to perform structure-function studies of intrinsically-disordered proteins, which are key-players of complex protein interactome and are involved in multiple human diseases.