From uncharted sequence space to de novo proteins

Biological proteins form mostly tightly clustered families in the pool of possible combinations of canonical amino acids. The sequence space of this alphabet provides far more options for de novo gene birth and design and is being extensively exploited. This quest is currently guided by the knowledge that has been accumulated by studying the natural biological proteins and can be significantly expanded by exploring the “dark protein space”, i.e protein sequence space unexplored by Nature. 

We performed high-throughput in vitro and in vivo structural screening of large combinatorial library of random sequence proteins with (i) biological amino acid composition and (ii) its limited versions. The assays map the biophysical properties of random sequences, such as solubility and structure-forming propensity. Libraries enriched in high expression, solubility and compaction are used to generate embeddings, leveraging state-of-the-art language models with the aim to navigate towards viable proteins.

About the speaker: Prof. Klara Hlouchova heads the group of Synthetic Biology at the Department of Cell Biology at Charles University in Prague. She obtained her PhD from the Czech Academy of Science and did postdoctoral research on the molecular evolution of enzymes with Prof. Shelley Copley at the University of Colorado, Boulder. The research of her group focuses on the evolution of protein structure and function, co-evolution of RNA and proteins in the context of the origin of life, and the effect of reduced and alternative amino acid alphabets on protein fold and function.

Klara will be at ETH in Zurich on 2nd April (Wed) and in Basel on 3rd and 4th April (Thu/Fri). If you would like to meet her, please sign up for a time slot here:

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