PhD Project - PhD position available in Experimental and Computational Organic Materials Discovery at Imperial College London, listed on FindAPhD.com

Study by biotech firm Monte Rosa finds that they can target a wider variety of proteins

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Life on Earth depends on chemical communication and the ability of biomolecular switches to integrate various chemical signals that trigger their activation or deactivation over time scales ranging from microseconds to days. The ability to similarly program and control the kinetics of artificial switches would greatly assist the design and optimization of future chemical and nanotechnological systems. Two distinct structure-switching mechanisms are typically employed by biomolecular switches: induced fit (IF) and conformational selection (CS). Despite 60 years of experimental and theoretical investigations, the kinetic and evolutive advantages of these two mechanisms remain unclear. Here, we have created a simple modular DNA switch that can operate through both mechanisms and be easily tuned and adapted to characterize its thermodynamic and kinetic parameters. We show that the fastest activation rate of a switch occurs when the ligand is able to bind its inactive conformation (IF). In contrast, we show that when the ligand can only bind the active conformation of the switch (CS), its activation rate can be easily programmed over many orders of magnitude by a simple tuning of its conformational equilibrium. We demonstrate the programming ability of both these mechanisms by designing a drug delivery vessel that can be programmed to release a drug over different time scales (>1000-fold). Overall, these findings provide a programmable strategy to optimize the kinetics of molecular systems and nanomachines while also illustrating how evolution may have taken advantage of IF and CS mechanisms to optimize the kinetics of biomolecular switches.