Rotating Molecular Tweezers for Diamino Substrates: An Allosteric Twist

Molecular tweezers are artificial receptors designed to bind small molecules (substrates) via non-covalent forces. Using synthetic organic and supramolecular chemistry, molecular tweezers can be designed from the bottom up to perform a specific function at the nanoscale. This makes them attractive candidates for molecular machines, as well as showing promise for applications in catalysis, as enzyme mimics, and as agents for targeted drug delivery and controlled release. We are particularly interested in developing molecular tweezer receptors which are selective for substrates of a specific size and/or shape.

Guided by molecular modelling we identified several key architectures, all of which contained bis-porphyrin receptors linked via a bridged polycyclic backbone with a central phenyl diimide core. The ability of the tweezers to freely rotate depends on the absence or presence of sterically bulky substituents on the phenyl core. We then successfully synthesised three structural analogues; a freely rotating tweezer with one binding site [1], a rotationally restricted tweezer with non-interconvertible syn- and anti- forms, and a rotating allosteric tweezer with two binding sites (Figure 1). Each tweezer binds diamine substrates, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), with large association constants.


Figure 1 – Molecular Structure of the Allosteric Porphyrin Tweezer with Two Binding Sites. Space Filling Molecular Model of the 1:2 complex formed between allosteric tweezer and DABCO, allosteric:(DABCO)2 (equilibrium geometry, semi-empirical AM1).

Titration of a solution of DABCO to a solution of allosteric tweezer in chloroform resulted in a red shift of the UV-Vis spectrum (inlaid Figure 2), characteristic of a bis-porphyrin DABCO sandwich complex [2], such as 1:2 or 2:2 (shown in blue). The sandwich complex is stable in the presence of a modest excess of DABCO, after which it is slowly converted to an open complex where DABCO is bound to each porphyrin singly, such as 1:4 (shown in green), as suggested by the second redshift of UV-Vis spectrum [2].


Figure 2 – Schematic Representation of the (Tweezer)x:(Substrate)y complexes formed upon mixing allosteric tweezer and DABCO, determined from curve fitting to UV-Visible spectroscopic titration data (inlaid).

The UV-Vis titration data was subjected to multivariate global spectral analysis curve fitting to determine the binding model and calculate the association constants for the tweezer-substrate interactions. The data gave reasonable fits with large association constants for the binding model 1:2 -> 1:4, as the concentration of DABCO is increased. An optional 2:2 intermolecular sandwich species could be included in the fitting; intermolecular sandwich complexes are known to form at UV-Vis concentrations (tweezer 10-7 M) but are generally much weaker than their intramolecular counterparts, in this case 1:2. The NMR titration data (not shown, tweezer concentration 10-4 M) suggested the formation of both major and minor sandwich complexes, most likely to be 1:2 and 2:2 respectively. We are currently undertaking mathematical analysis of the association constants to determine the allosteric cooperativity (negative or positive) within the 1:2 sandwich complex.

This work has been accepted for oral presentation and will be presented in full at the Royal Australian Chemical Institute National Congress 2014 (RACI2014) in Adelaide, Australia, 7-12 December 2014.

Article written by Rhys B. Murphy (PhD Candidate), supervisor Assoc Prof Martin R. Johnston.

[1] Murphy, R.B., Pham, D.-T., Lincoln, S.F., Johnston, M.R., Eur. J. Org. Chem., 2013, 2013 (15), 2985-2993.

[2] Ballester, P., et al., DABCO-Directed Self-Assembly of Bisporphyrins (DABCO = 1,4-Diazabicyclo[2.2.2]octane). Chem. Eur. J., 2005. 11(7): p. 2196-2206.

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