Synthetic ‘textbook model’ of a biological catalyst


exbox_enzyme

The cyclical ExBox lowers activation energy for the inversion of corannulene - speeding the reaction up 10-fold © NPG

Scientists have developed a simple two-molecule chemical analogue of an enzyme and its substrate that neatly illustrates the fundamental principles of biological catalysis.1 The reaction provides a synthetic model of a biological catalyst for students of biochemistry that is simple to visualise and understand and, according to one expert, is likely to become a ‘classic illustration’ of the tenets of enzyme catalysis. The model could also open new approaches to biomimetic catalysts.

In 1948 Linus Pauling suggested that enzymes work by binding transition states more strongly than they bind their substrates, and 10 years later Daniel Koshland proposed that the conformation of an enzyme’s active site alters to accommodate the substrate – by an ‘induced fit’ mechanism. But demonstrating these ideas in protein catalysts has been difficult because of their vast size and complexity.

Now, researchers from the labs of Jay Siegel in Tianjin University, China, and the University of Zurich in Switzerland, and Fraser Stoddart at Northwestern University, US, have come up with a simple analogue to demonstrate these key dictums of biological catalysis.

The team used the rectangular cyclophane ExBox – an extended bipyridine box structure – as the ‘active site’. The bowl-shaped polycyclic aromatic hydrocarbon corannulene filled in as the substrate and bowl-inversion as the reaction. Corannulene nestles in the ExBox cavity, such that the bowl is slightly flattened and the cavity is slightly expanded to optimise binding – an induced fit. The flat transition state to inversion is stabilised within the cavity, which results in the inversion process being accelerated 10-fold by the ExBox.

This sequence of events, together with the associated binding energies of the ground state corannulene and its planar transition state, was confirmed by NMR, crystallography and isothermal calorimetry, and independently correlated computationally.

‘We are able to demonstrate in an incredibly simple system all the principles laid out for much more complex biosystems, and can tease out all the relevant parameters such as the relative contribution to the catalytic effect of the induced fit and the optimal binding of the planar transition structure,’ says Siegel.

Commenting on the study,2Lawrence Scott of Boston College in the US says: ‘ The simplicity of the system makes it so well-defined structurally, kinetically and computationally that it is destined to become a classic illustration of the tenets of enzyme catalysis.’

Rudolf Allemann, an enzymologist at Cardiff University in the UK, says the system is ‘a particularly intriguing and simple example of the combined effects of ground state destabilisation and transition-state stabilisation’. Allemann adds that while ‘the catalytic effect observed in this synthetic system falls significantly short of those typically achieved by enzymes, ExBox4+ may still guide the design of other synthetic agents that use nature’s tricks to catalyse chemical reactions’.


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