Project description
Insight into protein mechanics
Mechanical forces strongly influence how proteins fold, bind and control cellular behaviour. Emerging evidence indicates that unusual protein interfaces, known as catch bond, become stronger when pulled. However, their prediction or design is impossible with current data and models. The ERC-funded PHENOMECHANICAL project will create a high-throughput platform that measures protein-protein interactions under force. The novelty of this approach is that it will link protein mechanostability to a DNA-sequencing readout. This will support machine-learning approaches capable of inferring catch-bond behaviour directly from protein structure. The PHENOMECHANICAL novel approach will uncover the design rules of catch bonds and pave the way for engineering synthetic variants with tunable properties.
Objective
Mechanical forces that steer protein interactions and folding play pivotal roles in biology. They shape cellular fate, and are critical factors in both pathogen adhesion and immune response. Catch bonds, atypical interfaces that increase their bound lifetime under mechanical force, play a central role in these processes. At present, we have no model nor datasets large enough to predict if an interaction is a catch bond from its structure without doing experiments, let alone design new catch bonds.
Single molecule force spectroscopy (SMFS) methods investigate the mechanics of proteins involved in these processes. These techniques typically have high force resolution, but extremely low throughput. An exhaustive database of proteins characterized by SMFS in the past 30 years contains only 85 entries. The overall aim of this proposal is to establish methods that allow large scale measurement of the mechanics of protein-protein interactions under force, first on hundreds, and finally on thousands of catch bonds: library-scale mechanical phenotyping. The key innovation proposed here is to link mechanostability, that is bond lifetime under an externally applied force, to a DNA-sequencing based readout by coupling phenotype to sequencing-readable genotype. Force resolution will be comparable to established flow-stretching assays, while throughput will increase by at least 2 orders of magnitude.
The increased throughput will be leveraged to identify the design principles of catch bonds using de novo protein design. Ultimately, I aim to engineer new-to-nature de novo catch bonds with tunable lifetimes under force, which could find application in new biomaterials or as synthetic force-steered cell receptors. The interplay of design and high throughput testing will create large, hypothesis driven computational and experimental datasets of protein mechanics suitable to machine learning approaches, possibly opening ways to infer catch bonding behavior solely based on structure.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences computer and information sciences databases
- natural sciences biological sciences biochemistry biomolecules proteins
- engineering and technology industrial biotechnology biomaterials
- natural sciences physical sciences optics spectroscopy
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-STG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
80539 MUNCHEN
Germany
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