Objective Enzymes are remarkably efficient catalysts and their recent use in non-aqueous organic solvents is opening a tremendous range of applications in synthetic chemistry: since, surprisingly, most enzymes do not denature in these non-natural environments, new reactions involving e.g. water-insoluble reagents can be catalyzed, while unwanted degradation side reactions are suppressed.However, a key challenge for these applications is to overcome the greatly reduced catalytic activity compared to aqueous conditions. Empirically, adding activators such as salts or small amounts of water dramatically enhances the activity, but the underlying mechanisms have remained elusive, thus preventing a rational optimization.Through analytic modeling and numerical simulations, our project will provide the first atomic-scale detailed description of enzyme catalysis in organic solvents, including the key role of the environment. We will then use this unprecedented molecular insight to design rigorous new procedures for the rational engineering of systems with dramatically enhanced activities, both through optimized choices of solvents and additives, and through targeted protein mutations.Specifically, we will first rigorously establish the influence of enzyme flexibility on catalytic activity through an original model accounting for the dynamic disorder arising from conformation fluctuations. Second, we will provide the first molecular explanation of the commonly invoked “lubricating” action of added water. Third, the underlying mechanism of the much employed salt-induced activation will be determined, probably calling for a radical change from the currently used picture of a water-mediated action.Far-reaching practical impacts are expected for the numerous industrial syntheses already employing biocatalysis in non-aqueous media. Fields of science natural sciencesbiological sciencesgeneticsmutationnatural scienceschemical sciencescatalysisbiocatalysisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-PE4 - ERC Starting Grant - Physical and Analytical Chemical sciences Call for proposal ERC-2011-StG_20101014 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS EU contribution € 1 390 800,00 Address RUE MICHEL ANGE 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Principal investigator Damien Laage (Dr.) Administrative Contact Julie Zittel (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS France EU contribution € 1 390 800,00 Address RUE MICHEL ANGE 3 75794 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Principal investigator Damien Laage (Dr.) Administrative Contact Julie Zittel (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data