Project description DEENESFRITPL New computational approaches promise to revolutionise protein design Protein engineering has made spectacular progress, allowing researchers to design proteins with novel properties and behaviours, and for new purposes. However, attempts at learning how to introduce functions into genetically encodable proteins designed from scratch (de novo design) have lagged behind. The EU-funded HelixMold project plans to develop new computational approaches to address this challenge. The project's activities will allow the functionalisation of de novo designed proteins with high thermostability, extraordinary resistance to harsh chemical environments and high tolerance to organic solvents. Overall, the project's advances aim to revolutionise how proteins are generated for use in biotechnology and biomedicine. Show the project objective Hide the project objective Objective We propose to computationally design novel ligand binding and catalytically active proteins by harnessing the high thermodynamic stability of de novo helical proteins. Tremendous progress has been made in protein design. However, the ability to robustly introduce function into genetically encodable de novo proteins is an unsolved problem. We will follow a highly interdisciplinary computational-experimental approach to address this challenge and aim to:-Characterize to which extent we can harness the stability of parametrically designed helical bundles to introduce deviations from ideal geometry. Ensembles of idealized de novo helix bundle backbones will be generated using our established parametric design code and designed with constraints accounting for an envisioned functional site. This will be followed by detailed computational, biophysical, crystallographic and site-saturation mutagenesis analysis to isolate critical design features.-Develop a new computational design strategy, which expands on the Crick coiled-coil parametrization and allows to rationally build non-ideal helical protein backbones at specified regions in the desired structure. This will enable us to model backbones around binding/active sites. We will design sites to bind glyphosate, for which remediation is highly needed. By using non-ideal geometries and not relying on classic heptad repeating units, we will be able to access a much larger sequence to structure space than is usually available to nature, enabling us to build more specific and more stable binding/catalytically active proteins.-Investigate new strategies to design the first cascade reactions into de novo designs.This research will allow functionalization of de novo designed proteins with high thermostability, extraordinary resistance to harsh chemical environments and high tolerance for organic solvents and has the potential to revolutionize how proteins for biotechnological and biomedical applications are generated. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesmathematicspure mathematicsgeometry Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-STG - ERC Starting Grant Call for proposal ERC-2018-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Coordinator TECHNISCHE UNIVERSITAET GRAZ Net EU contribution € 1 499 414,00 Address Rechbauerstrasse 12 8010 Graz Austria See on map Region Südösterreich Steiermark Graz Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all TECHNISCHE UNIVERSITAET GRAZ Austria Net EU contribution € 1 499 414,00 Address Rechbauerstrasse 12 8010 Graz See on map Region Südösterreich Steiermark Graz Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
