Research Awards

Biophysicist Lukas Milles has been awarded a Starting Grant by the European Research Council (ERC) for his new research project at LMU. The funding is worth some 1.5 million euros. The ERC awards Starting Grants based on the scientific excellence of the applicant and of the proposed project. They are among the most prestigious research awards in Europe.

Determining protein mechanics more efficiently

Lukas Milles is Professor of De Novo Protein Design, leads a research group at LMU’s Gene Center Munich, and is a member of the BioSysteM Cluster of Excellence. He researches how to design completely new proteins with specific properties with the aid of artificial intelligence.

Lukas Milles, ERC Starting Grant recipient

Mechanical forces that control the interactions and folding of proteins play a key role in biology. They determine the fate of cells and are decisive factors in the infection processes of pathogens and the immune response to them. So-called catch bonds are particularly important in these processes. Catch bonds are atypical bonds which increase their lifetime with mechanical force, whereas one would intuitively expect their lifetime to decrease with force.

“Currently we possess neither models nor sufficiently large datasets to predict a catch bond based on protein structure alone, never mind synthetically design new catch bonds,” says Milles. Consequently, scientists investigate the protein mechanics experimentally in the laboratory. With single-molecule force spectroscopy (SMFS), it is possible to study the forces involved very precisely. However, the method is very slow and time-consuming. Correspondingly few protein interactions have been measured with this technique to date. A database with proteins that have been characterized using SMFS over the past 30 years contains scarcely more than 85 entries.

The overarching goal of PHENOMECHANICAL (Phenotyping of protein mechanics libraries to unravel the design principles of catch bonds) is therefore to compile a comprehensive library with datasets for thousands of protein-protein interactions. To this end, Milles plans to establish a method that can measure mechanical forces between proteins with high throughput: “The key innovation consists in linking the lifetime of a bond with DNA sequencing by coupling the phenotype to the sequenceable genotype.” The resolution will be comparable to established approaches, while the throughput will be accelerated by at least two orders of magnitude.

It is precisely this increased throughput that is used to identify the design principles of catch bonds using de novo protein design. “Ultimately, it’s my goal to develop synthetically designed catch bonds with adjustable lifetimes, which could be used in novel biomaterials or as synthetic cell receptors,” says Milles. “The combination of protein design and high-throughput analyses will establish large datasets for protein mechanics, which will be suitable for machine learning approaches and may thus open up new paths for predicting the catch bonding behavior from protein structure alone.”

For more information about Lukas Milles and his research, please visit the Milles lab website.