Projektbeschreibung
Vorhersagen zur Enzymdynamik
Der Bereich der industriellen Biotechnologie bewegt sich von der rein chemischen Katalyse zur Verwendung von Enzymen bei der Katalyse von Schlüsselreaktionen. Faktoren wie Kostensenkung, Umweltfreundlichkeit, Effizienz und Spezifität machen die Biokatalyse zu einer attraktiven alternativen Lösung. Das EU-finanzierte Projekt PREDACTED untersucht, wie Enzyme arbeiten, sich an unterschiedliche Umweltbedingungen anpassen und sich weiterentwickeln. Die Forschenden werden Simulationsmodelle entwickeln, mit denen sich die Enzymdynamik und die mit der Katalyse verbundenen Veränderungen vorhersagen lassen. Die Ergebnisse sollen zur Entwicklung verbesserter künstlicher Enzyme und zur Bewältigung wichtiger Herausforderungen im Zusammenhang mit der Verwendung von Enzymen, wie beispielsweise der Antibiotikaresistenz, beitragen.
Ziel
Enzymes are superlative catalysts, honed by billions of years of evolution to achieve high specificity and efficiency. Understanding how enzymes function and are adapted to different environments will be essential in developing biocatalysts for the circular economy and in combating drug resistance. Basic principles of catalysis and mechanistic understanding have come from experiments and simulations, and significant progress has been made in designing and evolving de novo protein catalysts. Truly predictive understanding is limited, however. There is a need for models able to predict, e.g. whether an enzyme is able to break down a particular antibiotic and how to inhibit it; temperature dependence of catalysis; how mutations affect activity and temperature optima; to understand how catalytic power evolves and use those principles in the development of new biocatalysts.
Theoretical developments, and emerging multiscale methods, provide a route to the predictive understanding required. Fundamentally, protein dynamics are vital, not in ‘driving’ reaction but rather as a fundamental facet of natural enzymes on which evolution acts. PREDACTED will simulate enzyme dynamics and dynamical changes associated with catalysis. We will (1) Investigate the adaptation of enzyme activity using the emerging theoretical framework of macromolecular rate theory, and develop simulation approaches to predict enzyme temperature optima, with relevance e.g. for understanding ecosystem response to climate change, and for the development of biocatalysts for practical industrial applications. (2) Develop predictive simulation models for enzymes responsible for antibiotic resistance, analyse allosteric effects and predict spectrums of activity. (3) Model antibiotic breakdown and inhibition of beta-lactamases (4) Apply the understanding developed in redesigning and engineering natural and artificial enzymes to test the catalytic principles and demonstrate how they can be applied in practice.
Wissenschaftliches Gebiet
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural scienceschemical sciencescatalysisbiocatalysis
- natural sciencesearth and related environmental sciencesatmospheric sciencesclimatologyclimatic changes
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
BS8 1QU Bristol
Vereinigtes Königreich