Center for Computational & Integrative Biology, Massachusetts General Hospital
Department of Molecular Biology, Massachusetts General Hospital
Department of Genetics, Harvard Medical School
Howard Hughes Medical Institute

replicating vesicles || RNA selection || protein selection & genomics

 

RNA Selections: What Next?

  • Protocell-related RNA selections (see Szostak et al. 2001 Nature)
  • Aptamer Biology

Protocell Related RNA Selections

Replicating RNA inside replicating vesicles: a protocell

  • ribozyme,membrane compatibility
  • coordination of replication rates
  • replicase evolution in a protocell

Current state-of-the-art in RNA-catalyzed RNA replication: A 2-domain ribozyme polymerase from the Bartel lab.

What Next?

  • More efficient synthesis of longer products
  • Increased fidelity
  • Co-optimization of polymerase and template activity
  • Reannealing of + and - strands
  • Strand separation or strand displacement synthesis
  • Primer availability
  • Primer and NTP substrates: import into vesicles

Nucleoside triphosphates
Nucleoside phosphorimidazolides
'Modern' substrates
Very polar
Low chemical reactivity
Prebiotic model substrates
Less polar, more permeable
High chemical reactivity


Direct Selection for a Ribozyme Polymerase


Linking Functions:

  • metabolic ribozymes
  • permeability regulators
  • structural RNAs

Aptamer Biology

How abundant are functional molecules in sequence space ?
How difficult is it to convert one activity to another related activity (e.g. one type of binder into another?)
How difficult is it to augment an activity?
Is there a relationship between the level of activity and the abundance of molecules in sequence space with that activity?
Does adding structure to libraries increase the likelihood of obtaining functional molecules?
What is the best way to select for very tight binding aptamers?
What can we learn by solving the 3D atomic resolution structures (e.g. by NMR)?
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© 2007 Szostak Lab