News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1999-2000
P.G. Schultz, J.C. Anderson, S. Atwell, M. Berger, Y.T. Chang, L. Chen, A.
Deniz, S. Ding, M. Fa, A.E. Faulhaber, J. Gildersleeve, Z. Guo, T. Habicher,
B. Herberich, J. Janes, A. Kawamura, J. Liao, S. Licht, C. Loweth, D. Ly, T.
Magliery, A. Martin, E. Meggers, A. Ogawa, M. Pastrnak, J. Perl, R. Riedl, F.
Romesberg, S. Roy, S. Santoro, N. Segal, J. Semenova, A. Su, L. Supekova, F.
Tian, A. Ting, A. Varvak, L. Wang, C. Watanabe, Y. Wu, G. Xia, S. Yao, J. Yin,
The aim of our research is to combine the tools and principles of chemistry
with the molecules and processes of living cells to create molecules with new
properties and functions that occur neither naturally nor in the test tube. By
studying the structure and function of the resulting molecules, new insights
can be gained into the molecular mechanisms of complex biological and chemical
We showed that the tremendous combinatorial diversity of the immune response
can be chemically reprogrammed to generate selective enzymelike catalysts. We
developed antibodies that catalyze a wide array of chemical and biological reactions,
from acyl transfer to redox reactions, with specificities rivaling or exceeding
those of enzymes. Most recently, we focused on in vitro evolution methods that
involve the development of novel chemical screens and selections for detecting
mutants with enhanced function. The characterization of catalytic antibodies
is also providing insights into the mechanisms and evolution of naturally occurring
Our work on catalytic antibodies redirects natural combinatorial diversity
to produce new function. We are extending this combinatorial approach to many
other problems, including the generation of sequence-specific recombinases, small-molecule
regulators of biomolecular interactions, and RNA viruses. We are generating structure-based
libraries of small molecules that are being used in conjunction with novel protein
and cellular screens to identify inhibitors of important proteins involved in
cellular processes, including differentiation, proliferation, and signaling.
X-ray crystallography, biochemical studies, and genomics experiments are being
used to characterize the mode of action of these compounds and to study their
effects on cellular processes. We are also developing and applying modern genomics
and proteomics tools to a variety of important biomedical problems, including
aging, angiogenesis, stem cell differentiation, and viral infectivity.
We also developed a general biosynthetic method that makes it possible to
site-specifically incorporate unnatural amino acids into proteins. In the past
few years, we effectively expanded the genetic code to include more than 80 unnatural
amino acids with novel backbone and side-chain structures. We recently applied
the method to studies of the catalytic properties, specificity, and stability
of a number of proteins.
Currently, we are attempting to engineer a novel organism with orthogonal
tRNAs, synthetases, and codons that can uniquely use electrophilic keto, heavy
atom-binding, and fluorescent amino acids in its genetic code. This work takes
advantage of the power of organic chemistry and biology to manipulate large systems
of molecules to generate new cellular functions. In addition, in collaboration
with F. Romesberg, the Skaggs Institute, we began a project to generate an orthogonal
third base pair that is thermodynamically stable and can be replicated enzymatically
with high fidelity.
Finally, we are combining our ability to selectively manipulate the chemical
structures of proteins and nucleic acids with single-molecule optical spectroscopy
to study the structure and dynamics of individual protein and DNA molecules.
This research includes studies of catalysis, DNA recognition, protein folding,
and protein synthesis. The results may provide new insights into biomolecular
function that cannot be obtained by studying molecular ensembles.
Deniz, A.A., Dahan, M., Grunwell, J.R., Ha, T., Faulhaber, A.E., Chemla,
D.S., Weiss, S., Schultz, P.G. Single-pair fluorescence resonance energy
transfer on freely diffusing molecules: Observation of Förster distance
dependence and subpopulations. Proc. Natl. Acad. Sci. U. S. A. 96:3670, 1999.
Guo, Z., Zhou, D., Schultz, P.G. Designing small-molecule switches
for protein-protein interactions. Science 288:2042, 2000.
Liu, D.R., Schultz, P.G. Generating new molecular function: A lesson
from Nature. Angew. Chem. Int. Ed. 38:4000, 1999.
Liu, D.R., Schultz, P.G. Progress toward the evolution of an organism
with an expanded genetic code. Proc. Natl. Acad. Sci. U. S. A. 96:4780, 1999.
Ly, D.H., Lockhart, D.J., Lerner, R.A., Schultz, P.G. Mitotic misregulation
and human aging. Science 287:2486, 2000.