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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998


Molecular Recognition and Assembly


J. Rebek, Jr., C. Boss, M. Brody, R. Castellano, T. Heinz, G. Hilmersson, A. Luetzen, S. Ma, T. Martin, S. Mecozzi, D. Mink, B. O'Leary, U. Obst, K. Pryor, D. Pupowicz, J. Rivera, D. Rudkevich, J. Santamaria, C. Schalley, T. Szabo, J. Toker, F. Tucci, B. Vauzeilles, S. Waldvogel, S. Wallbaum, A. Wartini, P. Wash

How--and why--molecules fit together is a key question that lies at the heart of all biochemical phenomena and defines the science of molecular recognition. Our research has been concerned with these questions in the context of self-assembling, self-replicating, and informational molecules. In some ways the ultimate "fits" occur when one molecule completely surrounds another, and we have been using molecule-within-molecule complexes to test these limits of molecular recognition.

Most likely, molecular recognition was also an important step in prebiotic chemistry, because molecular surfaces that are in contact with each other are hidden from water and are protected from harmful exposure to hydrolytic agents. Molecules had survival as the first order of business, and when molecules large enough for sophisticated recognition were assembled, information could be embedded within them, and functions such as replication could develop.

In the past year, we have been using molecule-within-molecule complexes to explore the nature of the liquid state. How much space is filled and how much is empty in a typical liquid?

The answer has emerged through the behavior of our molecule-within-molecule encapsulation complexes and from the study of a number of solvents. We found that molecular assemblies are most stable when about 55% of the volume inside is occupied; that way molecules inside a capsule have as much freedom to "tumble" as they do outside, in the bulk of the solvent.

We have also studied the means by which molecules inside exchange positions with molecules outside. In the smallest of our systems, we can show that a "flap" opens on the structure and the molecule inside is displaced in an orderly fashion by an incoming molecule. In this sequence, vacuums and overcrowding are averted, and events take place in a predictable sequence. Figure 1 shows such an open flap in the smallest of our molecular capsules, the "tennis ball."

Asymmetry and handedness are common features of naturally occurring molecules, and we have been concerned with means by which asymmetry can be introduced into the molecule-within-molecule complexes. Asymmetry on the outer surface was easiest to arrange; then asymmetry in the lining of the cavities could be achieved. Ultimately, an asymmetric cavity was synthesized and tested for its encapsulation of small-molecule guests. An example of the behavior of these toward naturally occurring (handed) molecules is the preferential encapsulation of camphor in 1 of 2 possible "softball" mirror images (Fig. 2).

We also continue to explore solution-phase combinatorial chemistry and strive to make the synthesis and screening of large mixtures of molecules more and more efficient. Some new core molecules have been prepared (Fig. 3). With the help of collaborators, we were able to use the latest developments of mass spectrometry to characterize individual members of these libraries. Screening of synthetic mixtures for biological activity provides challenges and rewards; it offers speed but places restrictions on the assays used.

Finally, we are studying how molecules come together during reactions by positioning the reactants on a large molecular scaffold. As shown in Figure 4 (arrows), the amine at one end of the molecule reaches an acyl group at the other end of the molecule. The transfer of the acyl group takes place quite efficiently even though some 34 atoms intervene.

The efficiency is attributed to the orientation of the reacting groups; they are directed at each other by the rigidity of the scaffold and are held in place by the intramolecular hydrogen bonds.

Publications

Castellano, R.K., Kim, B.H., Rebek, J., Jr. Chiral capsules: Asymmetric binding in calixarene-based dimers. J. Am. Chem. Soc. 119:12671, 1997.

Castellano, R.K., Rudkevich, D.M., Rebek, J., Jr. Polycaps: Reversibly formed polymeric capsules. Proc. Natl. Acad. Sci. U.S.A. 94:7132, 1997.

Conn, M.M., Rebek, J., Jr. Self-assembling capsules. Chem. Rev. 97:1647, 1997.

Fang, A.S., Vouros, P., Stacey, C.C., Kruppa, G.H., Laukien, F.H., Wintner, E.A., Carell, T., Rebek, J., Jr. Rapid characterization of combinatorial libraries using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. Comb. Chem. High Throughput Screening 1:23, 1998.

Kang, J., Hilmersson, G., Santamaria, J., Rebek, J., Jr. Diels-Alder reactions through reversible encapsulation. J. Am. Chem. Soc. 120:3650, 1998.

Mecozzi, S., Rebek, J., Jr. The 55% solution: A formula for molecular recognition in the liquid state. Chem. Eur. J. 4:1016, 1998.

Pryor, K.E., Shipps, G.W., Skyler, D.A., Rebek, J., Jr. The activated core approach to combinatorial chemistry: A selection of new core molecules. Tetrahedron 54:4107, 1998.

Rivera, J.M., Martin, T., Rebek, J., Jr. Chiral spaces: Dissymmetric capsules through self-assembly. Science 279:1021, 1998.

Shipps, G.W., Jr., Pryor, K.E., Xian, J., Skyler, D.A., Davidson, E.H., Rebek, J., Jr. Synthesis and screening of small molecule libraries active in binding to DNA. Proc. Natl. Acad. Sci. U.S.A. 94:11833, 1997.

Szabo, T., Hilmersson, G., Rebek, J., Jr. Dynamics of assembly and guest exchange in the tennis ball. J. Am. Chem. Soc. 120:6193, 1998.

Tokunaga, Y., Rudkevich, D.M., Santamaria, J., Hilmersson, G., Rebek, J., Jr. Solvent controls synthesis and properties of supramolecular structures. Chem. Eur. J. 4:1449, 1998.

 

 







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