COCOA: Katalyyttien kontrollointi anionien avulla (COCOA)
Päärahoittaja
Rahoittajan antama koodi/diaarinumero: 339893
Päärahoittajan myöntämä tuki (€)
- 231 597,00
Rahoitusohjelma
Hankkeen aikataulu
Hankkeen aloituspäivämäärä: 01.09.2021
Hankkeen päättymispäivämäärä: 31.08.2025
Tiivistelmä
llostery and flexibility are two of the most fundamental drivers of enzyme evolution. The conformational flexibility of enzymes enables them to increase their catalytic power by using the binding energy of remote parts of their substrates and by the binding of allosteric activators. Based on the importance of allosteric regulation for the enzymatic machinery in Nature, we hypothesize that anion- responsive regulatory allosteric subunits could also be utilized as control domains in synthetic systems. In Nature, enzymes evolve by merging and splicing of different domains. We could do the same synthetically by fusing an allosteric domain with another functional domain, such as an organocatalyst. To test this concept, we will introduce allosteric regulation into three different functional domains: 1) small-molecule organocatalysts, 2) domains with pH-sensitive, covalently bound anions (functioning as molecular switches) and 3) enzyme activating domains. In all systems, we will introduce the same regulatory subunit that we have previously described and that adopts different conformations upon binding of different anions.
Through an intimate contact between the regulatory and functional units, we aim to control the optimization and regulation of both selectivity and activity of organocatalysts beyond simple on-off switching. The molecular switches with pH-sensitive anions would be able to respond to two different signals simultaneously: pH and the regulatory anions. Finally, anion-responsive activators whose shape could be modulated, are proposed for the controlled activation of CoA-dependent enzymes. Here, the functional domain would bear the 3’-phospho-adenosine end of CoA and the complete activator would introduce an allosteric control element – not in the enzyme but in the activator that binds to a part of the active site.
Computer simulations, in combination with solution and crystallographic structural studies, will be used at all stages of the research project to understand the properties of our synthetic allosteric systems at the atomic level and to guide the designs by predicting the most fruitful directions for structural modifications and by predicting the choice of controlling anions.
After demonstrating the concepts of allosteric modulation via anions, we will pursue a multitude of applications of the allosterically controlled species in small-molecule catalysis, anion recognition and sensing, and enzymatic catalysis.
Through an intimate contact between the regulatory and functional units, we aim to control the optimization and regulation of both selectivity and activity of organocatalysts beyond simple on-off switching. The molecular switches with pH-sensitive anions would be able to respond to two different signals simultaneously: pH and the regulatory anions. Finally, anion-responsive activators whose shape could be modulated, are proposed for the controlled activation of CoA-dependent enzymes. Here, the functional domain would bear the 3’-phospho-adenosine end of CoA and the complete activator would introduce an allosteric control element – not in the enzyme but in the activator that binds to a part of the active site.
Computer simulations, in combination with solution and crystallographic structural studies, will be used at all stages of the research project to understand the properties of our synthetic allosteric systems at the atomic level and to guide the designs by predicting the most fruitful directions for structural modifications and by predicting the choice of controlling anions.
After demonstrating the concepts of allosteric modulation via anions, we will pursue a multitude of applications of the allosterically controlled species in small-molecule catalysis, anion recognition and sensing, and enzymatic catalysis.
