Sagar D. Khare, Assistant Professor
Department Chemistry & Chemical Biology
Rutgers, The State University of New Jersey
Computational design of novel protein functions
After a few billion years of evolution, natural proteins solve the challenges biology has faced exceptionally well. The ability to computationally design novel protein functions would aid in rapidly meeting new functional challenges and is a rigorous test of our understanding of the underlying physical-chemical principles of interactions within and between biomolecules. I will describe two recent efforts towards the biophysics-based design of novel protein functions.
(a) We designed binding sites for the steroid drug digoxigenin in a set of protein structures derived from the Protein Databank. The guiding design criteria were high geometric shape complementarity, binding site pre-organization and calculated affinity. Upon experimental characterization, two designed proteins bound the steroid, and affinity could be improved to a picomolar level using library screening and deep sequencing. Crystal structures of two variants of one designed binder show atomic-resolution agreement with the corresponding design models.
(b) In ongoing work, we aim to develop protease enzymes with arbitrary dialed-in substrate specificities. The US FDA has approved twelve proteases as drugs and several others are in the pipeline. By virtue of catalytic turnover, a protease drug would be required in much lower dosages than binding-based drugs such as antibodies that are required in stoichiometric amounts. A key property for a protease that determines its therapeutic scope and possible toxicity is its substrate specificity. We have developed a simple, structure-based biophysical model that recapitulates the known sequence specificity of natural proteases, indicating that this model can now be applied to the design of novel protease specificities. I will describe our multi-state computational design approach for specificity modulation and high throughput experimental assays for testing our designs.
|Time : Tuesday, November 05, 2013, 01:00pm - 02:00pm|
|Location : Laufer Center Lecture Hall 101|
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