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The Chemical Biology of
Protein Synthesis.
Research in the Roberts lab
focuses on the protein synthesis machinery both as a tool for polypeptide design
and as a target that can be probed using chemical means. A key aspect of my lab's
work is peptide and protein design using in vitro selection experiments.
Toward this end, we use mRNA display, a technique the PI conceived and
implemented to enable polypeptide design (see figure below). This approach allows
the lab to create and sieve more than 10 trillion independent peptide or protein
sequences for function, the most of any technique currently available. In applying
any design approach, it is optimal if key issues, including affinity, specificity,
diversity, structure, dynamics, and biological activity can be addressed in a
principled way. The lab desires to execute a research program that tackles all
of these issues.
Our passion is using the tools of chemistry to understand and control biological
processes. We have applied our design approach to address biological control,
molecular recognition, stability, and dynamics in RNA-peptide complexes, G proteins
and G protein coupled receptors (GPCRs). In the future, our efforts should provide
new tools for systems biology and leads for therapeutic development.
mRNA display. An mRNA template (black line)
covalently attached to puromycin is used to program an in vitro translation
reaction. After protein synthesis, the puromycin enters the ribosome in cis
to form a covalent mRNA-protein fusion.
We are also very interested to re-engineer the protein
synthesis machinery to create unnatural mRNA display libraries. This
project, a nanoscale engineering effort, works to merge the power of display
selections with the flexibility of combinatorial chemistry. To do this, the
lab has worked to extend mRNA display beyond the natural genetic code, in an
effort to create new and richly diverse compositions of matter for ligand design,
drug discovery, and beyond.
In conjunction
with our re-engineering efforts, we have become intensely interested in thinking
about the ribosome as a target for puromycin analogues. Our work began
with efforts to understand the ribosome's substrate specificity. These efforts
have also yielded unexpected and exciting new reagents that have enabled us
to visualize protein synthesis in vivo in T-cells and neurons
with spatial and temporal resolution.
Finally, the PI's intellectual interest in evolution and the origin
of life has lead to work on a model for the origin of the ribosome and a
proposal for how Darwinian evolution could have begun via coupling genome replication
and cellular growth.
Overall,
research in the Roberts lab bridges Chemistry, Biology, and Engineering
with the goal of bringing new approaches to molecular design, systems biology,
and therapeutics. We have pursued these goals in both formal and informal collaborations
with other labs including (J. Alberola-Ila, S. Benzer, P. Bjorkman, D. Dougherty,
B. Hay, E. Schuman, A. Varshavsky, A. H. Zewail, S. R. Sprang N. Strynadka,
J. W. Szostak, and L. Jan).
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