Objective
Understanding, predicting and engineering protein-protein interaction (PPI) affinity and specificity is a key problem in molecular biology. In particular, we do not know how sequence-to-affinity encoding works at a quantitative and mechanistic level and we cannot predict and engineer the effects of mutations on PPIs. To tackle this problem, we need to generate large amounts of quantitative biophysical measurements. Until now this was not possible due to the low throughput of classic biophysics techniques. Here we propose to expand high-throughput deep mutational scanning (DMS) methodology to quantify the effects of tens of millions of mutations on hundreds of PPIs.
To generate a dataset of sufficient size and diversity to train models to predict changes in binding affinity from sequence, we will perform combinatorial trans mutagenesis by combining single mutants in the interaction interface of each partner of a given PPI and quantify the change in binding using a highly-validated protein complementation assay (PCA). To establish the platform, we will first focus on mutating PPIs of the KRAS oncoprotein. We will then scale up this approach to mutate at least one hundred structurally diverse PPIs. The resulting dataset will be of unprecedented size and standardisation, serving as a landmark reference dataset for us and others to train and evaluate models to predict the effects of mutations on interaction affinity. These data and models should transform our ability to understand clinical variants affecting PPIs and allow us to better understand, drug and engineer PPIs critical for medicine and biotechnology.
“DeepScalePPIs” will be supervised by Prof. Ben Lehner (CRG, Barcelona), whose group has pioneered the use of deep mutagenesis to understand protein structures, dynamics and interactions. In this unique environment I will be able to learn and combine knowledge from different fields s as genomics, systems biology, biophysics and computational biology.
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 biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences biophysics
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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Topic(s)
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.
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-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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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) HORIZON-MSCA-2024-PF-01
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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.
08003 Barcelona
Spain
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.