News and Publications
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.
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,
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.