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Overview
Herschlag lab: The Chemical and Physical Behavior of Biological Macromolecules
Premise:
To fully and deeply understand biology we must understand the fundamental behavior of its constituents. Further, our understanding is largely derived from comparison, and these comparisons are made at different levels of detail and from different perspectives.
Focus:
Comparing the behavior of functional RNA molecules in folding and catalysis to the vast information available for protein folding and catalysis will illuminate both classes of macromolecules. The differences help identify features unique to each class, and the similarities may represent properties fundamental to biology.
Mechanistic enzymology is poised to attack the vast functional questions now awaiting study in the post-genome era and is ripe for further development, through coupling of chemical and biophysical tools with classical kinetic, thermodynamic and structural approaches.
Finally, the same kinetic and quantitative principles applied at the molecular level will be required to unravel and fully understand the biological behaviors and properties that emerge at the systems level.
Goals:
To understand the fundamental behavior of RNA and proteins and the resulting biological ramifications.
Areas & Systems:
•RNA folding
Tetrahymena group I ribozyme, model RNA systems (biophysics, kinetics, etc)
•RNA catalysis
Tetrahymena group I ribozyme catalysis and self-splicing (biochemistry, kinetics, etc)
•Protein catalysis & evolution (biophysics; chemistry; kinetics; bioinformatics, etc)
Dissection of the Alkaline Phosphatase superfamily: Cognate & promiscuous activities
Ketosteroid isomerase: Unique probes of structure-function in catalysis
•RNA processing & emergent biological function (high throughput analysis, in vivo probing, etc)
Techniques (with collaborators):
Pre-steady state kinetics
Chemical probing of RNA structure
Fluorescence intensity & anisotropy
Single molecule fluorescence & FRET
Time resolved & static small angle x-ray scattering
Vibrational spectroscopy
Solid phase protein synthesis:
Unnatural amino acid incorporation
NMR
Chemical & novel probes of RNA dynamics
X-ray crystallography; EXAFS
Organic synthesis
Computation
High throughput microfluids, etc
General biochemistry & molecular biology