D-novo minibinders: developing a high throughput platform for computational design and production of tailored synthetic proteins

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Molecular discovery is at the forefront of chemical biology creating binders that can be applied in medicinal chemistry and drug discovery research. While proteins reach high affinity and specificity and act as almost universal binders in Nature, their size, immunogenicity and low stability can represent a drawback in developing diagnostics and therapeutics. Small molecules and D-amino acid - based peptides, in contrast, provide extreme control on the synthesis side and resistance to proteases, but their small size and flexibility can hinder the affinity to the target and limit their specificity.In this project we aim to combine the features of both systems and develop a computational and experimental platform for design and screening of stable D-amino acid based miniproteins as tailored binders (D-novo minibinders). This project will combine computational de novo design of miniprotein (40-60 residues) and binding interfaces with high throughput peptide synthesis and characterization. The student will learn how to analyze and manipulate structure in the Rosetta modelling suite and to synthesize, purify and characterize peptides and proteins.Our aim is to develop a rapid and robust computational and experimental pipeline for design of novel synthetic binders that might represent the next generation of therapeutics.