News and Publications

Studies in Molecular Recognition

Emergent Autocatalysis

When a molecule catalyzes its own formation, the reaction is termed autocatalysis; when molecular recognition is also involved, then the reaction is termed self-replication. Replication lies at the heart of prebiotic events on Earth, the events that gave birth to biology from chemistry. We encountered a new form of autocatalysis involving molecules within molecules: A reaction product accelerates its own formation, and it does so through molecular recognition. Is this replication? The key to the new phenomenon lies in the behavior of encapsulated reagents. When reagents are in the capsules they are turned "off"; when they are free in solution, they are turned "on."

In Figure 1, encapsulated dicyclohexylcarbodiimide (DCC) is displaced from the capsule by its reaction products. A single molecule of DCC reacts to yield 1 molecule each of dicyclohexyl urea and the anilide. Each of these molecules displaces DCC, leading to more urea and anilide in chain reaction kinetics. A sigmoidal reaction profile is the result. The nonlinear kinetics is a form of amplification and is governed by the strict recognition requirements of the capsule. Unlike other autocatalytic, self-replicating systems, the new behavior is not a property of a single molecule but emerges from the interactions of many molecules.

Targeting Proteins

A vast number of proteins have been brought to light through the sequencing of the human genome, and the current era is that of proteomics. Increasingly, the interactions of proteins with other proteins are implicated in disease. Curing these diseases may involve either disrupting or stabilizing the protein-protein interactions; the future lies in controlling these interactions.

Our premise is that small, synthetic druglike molecules most likely will not disrupt protein-protein interactions. The surface areas involved are too large, and small molecules can offer only small attractions for binding to protein surfaces. Accordingly, we are making scaffold molecules that present large surface areas with functional groups that all protrude from the same face of the scaffold (Fig. 2).

These functional groups can be incorporated through combinatorial chemistry to complement the groups on the protein surface.

Functional Cavitands

Cavitands are open-ended container host compounds that more or less surround small guest molecules. The binding that occurs involves weak intermolecular forces between host and guest, and this step is the first one on the road to the use of cavitands as reaction vessels. The second step requires functional groups that converge on the bound guest molecule and allow chemical reactions to occur.

In recent years, we made "functionalized" cavitands: cavitands with acids, bases, and metal ions directed inwardly to make contact with the guest. A cavitand with a porphyrin attached is shown in Figure 3.

The porphyrin binds metal ions that can act as catalysts and additional binding sites. The cavitand surrounds the adamantane anchor of the guest, and the pyridine nitrogen is attracted by the metal. The result is binding of high affinity and selectivity.

Publications

Chen, J., Körner, S., Craig, S.L., Rudkevich, D.M., Rebek, J., Jr. Amplification from compartmentalized reagents. Nature, in press.

Cho, Y.L., Rudkevich, D.M., Rebek, J., Jr. Expanded calix[4]arene tetraurea capsules. J. Am. Chem. Soc. 122:9868, 2000.

Haberhauer, G., Somogyi, L., Rebek, J., Jr. Synthesis of a second-generation pseudopeptide platform. Tetrathedron Lett. 41:5013, 2000.

Haino, T., Rudkevich, D.M., Shivanyuk, A., Rissanen, K., Rebek, J., Jr. Induced-fit recognition with water-soluble cavitands. Chemistry 6:3797, 2000.

Hof, F., Nuckolls, C., Craig, S.L., Martin, T., Rebek, J., Jr. Emergent conformational preferences of a self-assembling small molecule: Structure and dynamics in a tetrameric capsule. J. Am. Chem. Soc. 122:10991, 2000.

Lücking, U., Rudkevich, D.M., Rebek, J., Jr. Deep cavitands for anion recognition. Tetrahedron Lett. 41:9547. 2000.

Lücking, U., Tucci, F.C., Rudkevich, D.M., Rebek, J., Jr. Self-folding cavitands of nanoscale dimensions. J. Am. Chem. Soc. 122:8880, 2000.

Lützen, A., Starnes, S.D., Rudkevich, D.M., Rebek, J., Jr. A self-assembled phthalocyanine dimer. Tetrahedron Lett. 41:3777, 2000.

Rafai Far, A., Rudkevich, D.M., Haino, T., Rebek, J., Jr. A polymer-bound cavitand. Org. Lett. 2:3465, 2000.

Rebek, J., Jr. Molecular recognition, replication and assembly through synthesis. In: Fundamentals of Life. Palyi, G. (Ed.). Elsevier, New York, in press.

Renslo, A.R., Tucci, F.C., Rudkevich, D.M., Rebek, J., Jr. Synthesis and assembly of self-complementary cavitands. J. Am. Chem. Soc. 122:4573, 2000.

Rudkevich, D.M., Rebek, J., Jr. Deep cavities and capsules. In: Calixarenes for Separations. Lumetta, G.L., Rogers, R.D., Gopalan, A.S. (Eds.). American Chemical Society, Washington, DC, 2000, p. 270. ACS Symposium Series 757.

Shivanyuk, A., Rebek, J., Jr. Reversible encapsulation in solution by self-assembling resorcinarene subunits. Proc. Natl. Acad. Sci. U. S. A. 98:7662, 2001.

Shivanyuk, A., Rissanen, K., Körner, S.K., Rudkevich, D.M., Rebek, J., Jr. Structural studies of self-folding cavitands. Helv. Chim. Acta 83:1778, 2000.

Somogyi, L., Haberhauer, G., Rebek, J., Jr. Improved synthesis of functionalized molecular platforms related to marine cyclopeptides. Tetrahedron 57:1699, 2001.

Starnes, S.D., Rudkevich, D.M., Rebek, J., Jr. A cavitand-porphyrin hybrid. Org. Lett. 2:1995, 2000.

Wash, P.L., Renslo, A.R., Rebek, J., Jr. Isolation of an acid/base complex in solution puts the brakes on nitrogen inversion. Angew. Chem. Int. Ed. Engl. 40:1221, 2001.