The Skaggs Institute for
Chemical Biology
Published by TSRI Press®. © Copyright 2005,
The Scripps Research Institute. All rights reserved.
Hillary Van Anda, Graduate Student,
The Skaggs Institute for Chemical Biology
Published by TSRI Press®. © Copyright 2005,
The Scripps Research Institute. All rights reserved.
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY 2005
THE SKAGGS INSTITUTE
FOR CHEMICAL BIOLOGY
S TA F F
Julius Rebek, Jr., Ph.D.*
Director and Professor
Kim D. Janda, Ph.D.*
Professor
Ely R. Callaway, Jr., Chair
in Chemistry
Gerald F. Joyce, M.D.,
Ph.D. †††
Professor
Carlos F. Barbas III, Ph.D.**
Professor
Janet and W. Keith Kellogg II
Chair in Molecular Biology
Ehud Keinan, Ph.D.**
Adjunct Professor
Ernest Beutler, M.D.***
Professor
Chairman, Department of
Molecular and Experimental
Medicine, Scripps Research
Jeffery W. Kelly, Ph.D.*
Vice President, Academic
Affairs, Scripps Research
Dean, Kellogg School of
Science and Technology
Lita Annenberg Hazen
Professor of Chemistry
Dale L. Boger, Ph.D.*
Richard and Alice Cramer
Professor of Chemistry
Geoffrey Chang, Ph.D.**
Assistant Professor
Benjamin F. Cravatt,
Ph.D.****
Associate Professor
Philip Dawson, Ph.D.*****
Assistant Professor
Gerald M. Edelman, M.D.,
Ph.D. †
Professor
Chairman, Department of
Neurobiology, Scripps
Research
Albert Eschenmoser, Ph.D.*
Professor
Martha J. Fedor, Ph.D.**
Associate Professor
M.G. Finn, Ph.D.*
Associate Professor
Hartmuth Kolb*
Associate Professor
Richard A. Lerner, M.D. †††
President, Scripps Research
Lita Annenberg Hazen
Professor of
Immunochemistry
Cecil H. and Ida M. Green
Chair in Chemistry
Stephen P. Mayfield,
Ph.D.*****
Associate Professor
Associate Dean, Kellogg
School of Science and
Technology
K.C. Nicolaou, Ph.D.*
Aline W. and L.S. Skaggs
Professor of Chemical Biology
Darlene Shiley Chair in
Chemistry
Chairman, Department of
Chemistry, Scripps Research
Paul R. Schimmel, Ph.D. †††
Ernest and Jean Hahn
Professor and Chair of
Molecular Biology and
Chemistry
RESEARCH
A S S O C I AT E S ††††
Dariush Ajami, Ph.D.
Elizabeth Barrett, Ph.D.
Peter Schultz, Ph.D.*
Professor
Scripps Family Chair
Sara Butterfield, Ph.D.
Alexandre Carella, Ph.D.
Clemens Haas, Ph.D.
K. Barry Sharpless, Ph.D.*
W.M. Keck Professor of
Chemistry
Subhash C. Sinha, Ph.D.**
Associate Professor
John A. Tainer, Ph.D.**
Professor
James R. Williamson, Ph.D.†††
Professor
Associate Dean, Kellogg
School of Science and
Technology
Ian A. Wilson, D.Phil.**
Professor
Chi-Huey Wong, Ph.D.*
Ernest W. Hahn Professor
and Chair in Chemistry
Peter E. Wright, Ph.D.**
Professor
Cecil H. and Ida M. Green
Investigator in Biomedical
Research
Chairman, Department of
Molecular Biology, Scripps
Research
Kurt Wüthrich, Ph.D. †††
Cecil H. and Ida M. Green
Visiting Professor of
Structural Biology
Frank Hauke, Ph.D.
Richard J. Hooley, Ph.D.
Enrique Mann, Ph.D.
Edoardo Menozzi, Ph.D.
Lionel Moisan, Ph.D.
Andrew Myles, Ph.D.
Hideki Onagi, Ph.D.
Dalit Rechavi-Robinson, Ph.D.
Riccardo Salvio, Ph.D.
Felix Zelder, Ph.D.
* Joint appointment in the
Department of Chemistry
** Joint appointment in the
Department of Molecular Biology
*** Joint appointment in the
Department of Molecular and
Experimental Medicine
**** Joint appointments in the
Departments of Cell Biology and
Chemistry
***** Joint appointment in the
Department of Cell Biology
†
††
†††
††††
Joint appointment in the
Department of Neurobiology
Joint appointments in the
Departments of Molecular
Biology and Immunology
Joint appointments in the
Departments of Chemistry and
Molecular Biology
Research associates in the laboratories of staff other than Dr.
Rebek are included in the lists
of the respective departments in
which the associates hold joint
appointments.
Elizabeth D. Getzoff, Ph.D.††
Professor
M. Reza Ghadiri, Ph.D.*
Professor
SECTION COVER FOR THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY:
A water-soluble synthetic receptor extracts alkanes from aqueous solution via hydrophobic effects.
Inside the cavity, the alkanes coil into a helix to maximize contacts with the receptor and tumble rapidly.
Work done by Richard J. Hooley, Ph.D., Research Associate in the laboratory of Julius Rebek, Jr., Ph.D.
Published by TSRI Press®. © Copyright 2005,
The Scripps Research Institute. All rights reserved.
11
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
In 1996, The Scripps Research Institute established The Skaggs Institute for Chemical Biology, made possible by a gift of more than $100 million to The Skaggs Institute for Research from Aline W. and L.S. Skaggs.
Scientific members of the Skaggs Institute hold dual appointments in various departments at Scripps
Research. These scientists have broad expertise in areas including the structure of biological macromolecules, chemical and antibody catalysis, synthetic and combinatorial chemistry, molecular recognition, and
molecular modeling methods. With the achievements of its staff, the Skaggs Institute has assumed its
research identity in the United States and throughout the world at the interface of biology and chemistry.
Published by TSRI Press®. © Copyright 2005,
The Scripps Research Institute. All rights reserved.
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY 2005
Julius Rebek, Jr., Ph.D.
Director’s Overview
he Skaggs Institute for Chemical Biology is entering its 10th year. The generous endowment of the
Skaggs family currently supports the research of
31 principal investigators, 85 graduate students, and
more than 140 postdoctoral fellows. These researchers
produced 334 publications during the past year in the
areas of chemistry, chemical biology, molecular biology,
and immunology. The individual reports of the principal
investigators are presented elsewhere in this volume,
but a few of the highlights are given here.
Albert Eschenmoser and members of his group are
studying the minimal requirements for a self-replicating,
informational biopolymer. Using a “bottom down” approach
and starting from the structure of current nucleic acids,
they are simplifying backbones and recognition elements
that are consistent with prebiotic molecules. The target
structures must pair not only to themselves but also to
RNA, and thereby provide the bridge that may have led
to the RNA world.
K. Barry Sharpless and his group have developed
ingeniously simple reactions “on water.” They find that
such reactions proceed optimally in contact with water,
particularly when the organic reactants are insoluble in
the aqueous phase. The origins of the rate accelerations
are being pursued here and worldwide.
T
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13
Dale Boger and colleagues have developed secondgeneration syntheses of antibiotics related to vancomycin.
They have pinpointed the molecular details of vancomycin
resistance and have now completed synthesis of a vancomycin derivative that can overcome this resistance.
This type of reengineering could be a model for the
medicines of the future.
Scientists in Ian Wilson’s group have solved the first
structure of a human Toll-like receptor. These spectacular molecules are members of signaling compounds that
activate the innate immune response. The horseshoeshaped structure recognizes RNA from microorganisms
and activates the immune cascade. The researchers have
reconstructed and analyzed the hemagglutinin from the
1918 Spanish flu virus. Their structural studies also target the avian influenza viruses that are currently prevalent in Asia.
Kim Janda and members of his laboratory have shown
that a simple metabolite of nicotine alters the balance
of retinoids in living systems. Specifically, nornicotine
was implicated in the underlying molecular mechanism
of age-related macular degeneration. Elizabeth Getzoff
and her group have sequenced a new gene for cryptochrome, a flavoprotein that is a component of circadian clocks in animals and humans. The scientists
determined the first crystal structure of the flavoprotein and found that the molecule has an unusual shape,
consistent with its function of surrounding DNA. The
ultimate goal is to find the chemical basis for biological
responses to light.
M.G. Finn and his colleagues have taken a novel view
of viruses and use them as molecular building blocks.
The proteins of virus particles can be modified by synthetic reactions to attach, for example, carbohydrates
that are selective markers for various cancer cells. These
particles are intended to have advantageous properties
for pharmacokinetics and for targeting cells in vivo. Kurt
Wüthrich and his group use nuclear magnetic resonance
to solve the structures of proteins in solution and study
the motions of the proteins. The self-splicing protein
elements, the inteins, are the current target. The proteins
adopt a horseshoe-shaped fold and undergo unusually
slow changes in shape as they are processed into the
fully active substances.
Researchers in the laboratory of Peter Schultz continue to expand the number of building blocks for proteins beyond those involved in the genetic code. The
researchers have prepared autonomous organisms capable of incorporating 21 amino acids, and they hope to
14 THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY 2005
optimize unnatural amino acid incorporation to even
mammalian cells.
Stephen Mayfield and his group have developed a
system for synthesizing proteins in algae. The molecules
can be generated in a short time and on a large scale.
The goal of the research is the production of monoclonal
antibodies; antibodies represent a large fraction of newly
approved drugs but are some of the most expensive
agents on the market. The research group of Richard
Lerner is expanding the application of catalytic antibodies to problems of drug delivery. Specifically, activation
of prodrugs can be catalyzed by these antibodies; the
intent is to target the prodrug and antibody specifically
to cells of interest.
A number of the Skaggs investigators have received
national and international recognition, and the graduate
program at Scripps Research continues to be at the top
in national surveys. The support of the Skaggs family has
enabled the emergence of The Skaggs Institute for Chemical Biology as one of the best research environments in
the United States. We continue moving our basic research
discoveries toward applications of cures for diseases.
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The Scripps Research Institute. All rights reserved.
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY 2005
15
INVESTIGATOR’ S REPORT
Molecular Encapsulation
J. Rebek, Jr., D. Ajami, E. Barrett, S. Biros, S. Butterfield,
A. Carella, T.J. Dale, C. Haas, F. Hauke, R.J. Hooley,
E. Mann, E. Menozzi, L. Moisan, A. Myles, H. Onagi,
L. Palmer, B. Purse, D. Rachavi-Robinson, R. Salvio,
H. Van Anda, F. Zelder
eversible encapsulation creates spaces where
molecules are temporarily isolated from others
in solution. The molecules are held within the
space of the capsule for lifetimes of milliseconds to
hours, and nuclear magnetic resonance spectroscopy
can indicate the chemical and magnetic environment
as well as the arrangement of molecules in the encapsulation complex. The complexes self-assemble only
when the spaces inside the capsules are appropriately
filled. Weak intermolecular forces hold these self-assemblies together, and the encapsulation complexes are at
equilibrium at ambient temperatures and pressures in
the liquid phase. When 2 or more molecules are coencapsulated, intermolecular phenomena are revealed in
solution that have not been observed with other methods. Unique behavior emerges, including new forms of
stereochemistry, isomerism, and asymmetry inside capsules. Encapsulation isolates, extends, and even amplifies interactions of molecules and reactions held at
close range.
We prepared a cylindrical capsule that assembles
from 2 molecules of the vaselike shape shown in Figure 1 when appropriate guests are present. The capsule accommodates 3 molecules of propylene sulfide
as guests, but these are fixed in space, one molecule
at each end and another in the middle. These guests
are too large to squeeze past one another, at least on
the nuclear magnetic resonance time scale. When a
racemic mixture of the propylene sulfide was used, 4
different diastereomeric arrangements were observed.
These arrangements in space are named constellations,
and the odd number of molecules inside has the inevitable consequence that each assembled capsule is
chiral. The different arrangements in space are hints of
information, and the capsules represent a short-lived
form of data storage on the nanometer scale.
We also have observed restrictions on spinning of
encapsulated molecules within the cylinder. The snug
fit of paracyclophane inside one end of the capsule is
R
Published by TSRI Press®. © Copyright 2005,
The Scripps Research Institute. All rights reserved.
F i g . 1 . Top, left, Synthesis and structure of a cylindrical capsule.
The peripheral alkyl groups impart solubility in organic solvents and
are not shown. Top, center, A belt of 8 bifurcated hydrogen bonds
holds the capsule together and presents a tapered cavity of 420 Å3.
Top, right, the schematic drawing of a capsule. Bottom, Diastereomeric constellations. Six possible arrangements are possible for propylene sulfide, a small chiral molecule, in the cylindrical capsule.
Each of the 4 assemblies shown contains both enantiomers and was
identified by using nuclear magnetic resonance spectroscopy. All
assemblies are chiral; an odd number of molecules is present in
each capsule.
shown in Figure 2. Any spinning of the cyclophane
forces a breathing motion of the capsule’s walls. When
the cyclophane is coencapsulated with carbon tetrachloride, the crowding pushes the cyclophane toward
the tapered end of the capsule and slows its spinning
rate. With a small coguest such as ethane, the spinning rate increases as the cyclophane is afforded more
space inside. By measuring the rate of spinning of the
cyclophane, the effective size of any coencapsulated
guest can be estimated.
F i g . 2 . Coencapsulated molecules affect the spinning of paracy-
clophane according to size. Left, The complex of carbon tetrachloride and paracyclophane (center). Right, The cyclophane in one
end of the capsule enjoys a snug fit that resists spinning.
16 THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY 2005
The use of 3 different guests can result in 18 different arrangements in the cylinder. We have observed
1 of these arrangements with 3 different guests inside:
isopropyl chloride, chloroform, and the hexafluorophosphate anion (Figure 3). No counterion is present inside
the capsule. Molecular encapsulation forces apart the
2 charges, and this cost is paid for by the interactions
of the anion with the seam of hydrogen bonds that hold
the capsule together.
Palmer, L.C., Rebek, J., Jr. The ins and outs of molecular encapsulation. Org. Biomol. Chem. 2:3051, 2004.
Purse, B., Rebek, J., Jr. Encapsulation of oligoethylene glycols and perfluoro-n-alkanes
in a cylindrical host molecule. Chem. Commun. (Camb.) 722, 2005, Issue 6.
Rebek, J., Jr. Simultaneous encapsulation: molecules held at close range. Angew.
Chem. Int. Ed. 44:2068, 2005.
Richeter, S., Rebek, J., Jr. Catalysis by a synthetic receptor sealed at one end and
functionalized at the other. J. Am. Chem. Soc. 126:16280, 2004.
Scarso, A., Onagi, H., Rebek, J., Jr. Mechanically regulated rotation of a guest in a
nanoscale host. J. Am. Chem. Soc. 126:12728, 2004.
Shivanyuk, A., Rebek, J., Jr. Molecular recognition of bulky phosphonium cations
by resorcinarenes. J. Org. Pharm. Chem. 2:7, 2004.*
Vysotsky, M.O., Mogck, O., Rudzevich, Y., Shivanyuk, A., Böhmer, V., Brody,
M.S., Cho, Y.L., Rudkevich, D., Rebek, J., Jr. Enhanced thermodynamic and
kinetic stability of calix[4]arene dimers locked in the cone conformation. J. Org.
Chem. 69:6115, 2004.
F i g . 3 . Encapsulation of 3 species. Left, Anions are coencapsu-
lated with the solvent chloroform. The anions occupy the center of
the capsule and interact with its belt of hydrogen bonds. Right,
When both chloroform and isopropyl chloride are present, a capsule with 3 different species occurs.
The behavior of even a single molecule is influenced
by confinement in this cylindrical capsule. For example, normal alkanes coil into helical structures to fit
within the capsule, whereas perfluorinated alkynes can
be accommodated in their ground states. The oligoethyleneglycols were also accommodated as the helical
structure shown in Figure 4.
F i g . 4 . Model structures of n-tridecane, tetraethylene glycol, and
perfluoro-n-octane in the cylindrical capsule.
PUBLICATIONS
Amaya, T., Rebek, J., Jr. Coencapsulation of three different guests in a cylindrical
host. Chem. Commun. (Camb.) 1802, 2004, Issue 16.
Amaya, T., Rebek, J., Jr. Hydrogen-bonded encapsulation complexes in protic solvents. J. Am. Chem. Soc. 126:14149, 2004.
Published by TSRI Press®. © Copyright 2005,
The Scripps Research Institute. All rights reserved.