New work on information transfer in molecules sheds light on enzyme reactivity
Allostery is one of the most intriguing properties of the molecular machinery of life. Bind an oxygen molecule to one of the four subunits that makes up the haemoglobin molecule, and the other three subunits will, as if by magic, know that it is there and behave differently.
In many enzymes, too, a change at one end of the molecule can affect the catalytic reaction at the other. Two research groups have now recreated remote effects in artificial molecules, one to create a well-defined chiral environment (comparable to binding sites like those of haemoglobin), the other to make catalysis controllable as in allosteric enzymes.
Jonathan Clayden and colleagues at the University of Manchester, UK, have succeeded in creating a molecule that transmits a piece of information over more than 20 bond lengths, or a distance of over 2.5nm. To achieve this, they made use of the observation that in polyaromatic systems with several amide functions the amides tend to arrange themselves orthogonally to the ring plane, and have a preference for alternating arrangements minimising the overall dipole moment. In a xanthene with two amide functions, around 95 per cent of the molecules adopt the anti conformation.
The Manchester group linked as many as three such xanthene building blocks together, resulting in an extended system with six bulky amides that can be switched up or down. While the relative configuration is likely to be predominantly anti, the absolute orientation remains random, such that each chain could start with up or with down. By attaching an oxazolidine ring of a given chirality to one end of the chain, the researchers forced one specific orientation onto the first amide. This resulted in the adjustment of the other amides, and the creation of a new stereogenic centre at the far end of the molecule. Here, a formyl group reacts in a highly diastereoselective manner, depending on the chirality information transmitted by the chain.1
Meanwhile, a group led by Chad Mirkin at the Northwestern University at Evanston, Illinois, US, designed a dimeric tweezer-shaped complex incorporating a catalytic centre at each end and a rhodium coordination site as a hinge that can be opened by the interaction with competing ligands.2
The researchers studied the catalytic efficiency of the closed tweezer dimer in comparison with both the open form and separate half-tweezers (monomers). The reaction required two catalysts per molecular encounter and found that closing the tweezer activates the catalyst.
However, in concentrated solution, the effect is somewhat weakened by the fact that chance encounters with two catalysts at the same time may also lead to successful reactions. Thus, the tweezer mechanism is most efficient in very dilute solutions. If the complex could be immobilised, it would represent the first non-biological catalyst with an allosteric on-off switch.
1 J Clayden et al, Nature, 2004, 431, 966
2 N C Gianneschi et al, Angew. Chem. Int. Ed., 2004, 43, 5503