Descripción del proyecto
Predicción de la dinámica enzimática
El campo de la biotecnología industrial está pasando de la catálisis basada solo en la química al uso de enzimas para catalizar las reacciones clave. Factores como la reducción de los costes, el respeto al medio ambiente, la eficacia y la especificidad convierten a la biocatálisis en una atractiva solución alternativa. El proyecto PREDACTED, financiado con fondos europeos, está interesado en comprender cómo funcionan las enzimas, cómo se adaptan a diferentes condiciones ambientales y cómo evolucionan. Los investigadores desarrollarán modelos de simulación que puedan predecir la dinámica enzimática y los cambios asociados con la catálisis. Los resultados contribuirán a diseñar mejores enzimas artificiales y a abordar los principales retos asociados con el uso de enzimas, como la resistencia a los antibióticos.
Objetivo
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.
Ámbito científico
- 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
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
BS8 1QU Bristol
Reino Unido