Molecular tweezers

Trinitrofluorene bound in molecular tweezers reported by Lehn and coworkers.[1]
A fullerene bound in a buckycatcher through aromatic stacking interactions Reported by Sygula and coworkers.[2]

Molecular tweezers, and molecular clips, are noncyclic host molecules with open cavities capable of binding guest molecules. The term "molecular tweezers" was first used by Howard J. Whitlock,[3] but the class of hosts was developed and popularized by Steven C. Zimmerman in the mid-1980s to early 1990s[4][5][6] and later by Frank-Gerrit Klärner and Colleagues.[7] The open cavity of the molecular tweezers may bind guests using non-covalent bonding which includes hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, and/or electrostatic effects. These complexes are a subset of macrocyclic molecular receptors and their structure is that the two "arms" that bind the guest molecule between them are only connected at one end leading to a certain flexibility of these receptor molecules (induced fit model).

Examples

One example of molecular tweezers has been reported by Lehn and coworkers. This molecule is capable of binding aromatic guests.[1] The molecular tweezers are composed of two anthracene arms held at a distance that allows aromatic guests to gain π-π interactions from both.

Another class of molecular tweezers is composed of two substituted porphyrin macrocycles tethered by an amide linker with a variable length. This example of a molecular tweezer shows the potential mobility of this class of molecules, as the orientation of the porphyrin planes which comprise the tweezer can be altered by the guest which is bound [8]

Yet another structure for molecular tweezers which specifically bind fullerenes is called a buckycatcher and has been reported.[2] This molecular tweezer is composed of two concaved corannulene pincers that complement the surface of the convex fullerene guest. An association constant (Ka) of 8600 M−1 between the host buckycatcher and a C60 fullerene was calculated using 1H NMR spectroscopy.

The water-soluble phosphate-substituted tweezer binds to the positively charged aliphatic sidechains of basic amino acids very selectively (to lysine stronger than to arginine) [9] whereas the molecular clip prefers to clip flat pyridinium rings (for example the nicotinamide ring from NAD(P)+) between its plane naphthalene sidewalls [10] These mutually excluding binding modes make these compounds valuable tools to probe critical biological interactions of lysines in peptides and on protein surfaces as well as of NAD(P)+ cofactors. For example, both compounds inhibit the oxidation reactions of ethanol or glucose-6-phosphate by NAD(P)+, which are catalyzed by alcohol dehydrogenase or glucose-6-phosphate dehydrogenase [11] respectively. In addition, the tweezer, but not the clip, prevents formation of misfolded oligomers and aggregates of amyloidogenic proteins, including those of amyloid β-protein (Aβ) and tau [12][13] and α-synuclein[14] which are thought to cause Alzheimer’s and Parkinson’s diseases, respectively.

The above examples show the potential reactivity and specificity of these molecules. The binding site between the planes of the tweezer can evolve to bind to an appropriate guest with resulting high association constants and consequent stability, depending on the configuration of the tweezer. That makes this overall class of macromolecule truly a synthetic molecular receptor.

References

  1. ↑ 1.0 1.1 A. Petitjean, R. G. Khoury, N. Kyritsakas and J. M. Lehn (2004). "Dynamic Devices. Shape Switching and Substrate Binding in Ion-Controlled Nanomechanical Molecular Tweezers". J. Am. Chem. Soc. 126 (21): 6637–6647. doi:10.1021/ja031915r. PMID 15161291.
  2. ↑ 2.0 2.1 A. Sygula, F. R. Fronczek, R. Sygula, P. W. Rabideau and M. M. Olmstead (2007). "A Double Concave Hydrocarbon Buckycatcher". J. Am. Chem. Soc. 129 (13): 3842–3843. doi:10.1021/ja070616p. PMID 17348661.
  3. ↑ Chen C.-W.; Whitlock H. W. "Molecular Tweezers - A Simple-Model of Bifunctional Intercalation," J. Am. Chem. Soc. 1978, 100, 4921
  4. ↑ Zimmerman, S. C.; VanZyl, C. M. "Rigid molecular tweezers: synthesis, characterization, and complexation chemistry of a diacridine," J. Am. Chem. Soc. 1987, 109, 7894.
  5. ↑ Zimmerman, S. C.; Wu, W. "A rigid molecular tweezers with an active site carboxylic acid: exceptionally efficient receptor for adenine in an organic solvent," J. Am. Chem. Soc. 1989, 111, 8054.
  6. ↑ Zimmerman, S. C. "Rigid molecular tweezers as hosts for the complexation of neutral guests," Top. Curr. Chem. 1993, 165, 71.
  7. ↑ F.-G. Klärner and B. Kahlert (2003). "Molecular Tweezers and Clips as Synthetic Receptors. Molecular Recognition and Dynamics in Receptor-Substrate Complexes". Acc. Chem. Res. 36 (12): 919–932. doi:10.1021/ar0200448. PMID 14674783.
  8. ↑ X. Huang, N. Fujioka, G. Pescitelli, F. Koehn, R. T. Williamson, K. Nakanishi and N. Berova (2002). "Absolute Configurational Assignments of Secondary Amines by CD-sensitive Dimeric Zinc Porphyrin Host". J. Am. Chem. Soc. 124 (17): 10320–10335. doi:10.1021/ja020520p.
  9. ↑ P. Talbiersky, F. Bastkowski, F.-G. Klärner, T. Schrader (2008). "Molecular Clip and Tweezer Introduce New Mechanisms of Enzyme Inhibition". J. Am. Chem. Soc. 130 (30): 9824–9828. doi:10.1021/ja801441j.
  10. ↑ J. Polkowska, F. Bastkowski, T. Schrader, F.-G. Klärner, J. Zienau, F. Koziol, C. Ochsenfeld (2009). "A combined experimental and theoretical study of the pH-dependent binding mode of NAD+ by water-soluble molecular clips". J. Phys. Org. Chem. 22 (30): 779–790. doi:10.1002/poc.1519.
  11. ↑ M. Kirsch, P. Talbiersky, J. Polkowska, F. Bastkowski, T. Schaller, H. de Groot, F.-G. Klärner, T. Schrader (2009). "A Mechanism of Efficient G6PD Inhibition by a Molecular Clip". Angew. Chem. Int. Ed. 48: 2886–2890. doi:10.1002/anie.200806175.
  12. ↑ S. Sinha, D. H. J. Lopes, Z. Du, E. S. Pang, A. Shanmugam, A. Lomakin, P. Talbiersky, A. Tennstaedt, K. McDaniel, R. Bakshi, P.-Y. Kuo, M. Ehrmann, G. B. Benedek, J. A. Loo, F. –G. Klärner, T. Schrader, C. Wang, G. Bitan (2011) (2011). "Lysine-Specific Molecular Tweezers Are Broad-Spectrum Inhibitors ofAssembly and Toxicity of Amyloid Proteins". J. Am. Chem. Soc. 133 (42): 16958–16969. doi:10.1021/ja206279b.
  13. ↑ Attar A, Ripoli C, Riccardi E, Maiti P, Li Puma DD, Liu T, Hayes J, Jones MR, Lichti-Kaiser K, Yang F, Gale GD, Tseng CH, Tan M, Xie CW, Straudinger JL, Klärner FG, Schrader T, Frautschy SA, Grassi C, Bitan G (2012) Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers. Brain 135:3735-3748. 10.1093/brain/aws289.
  14. ↑ Prabhudesai S, Sinha S, Attar A, Kotagiri A, Fitzmaurice AG, Lakshmanan R, Ivanova MI, Loo JA, Klärner FG, Schrader T, Stahl M, Bitan G, Bronstein JM (2012) A novel "molecular tweezer" inhibitor of α-synuclein neurotoxicity in vitro and in vivo. Neurotherapeutics 9:464-476. 10.1007/s13311-012-0105-1.

External links