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A minimal sequence code for switching protein structure and function

This paper explores a minimal sequence code for switching the structure and function of proteins. By mutating stable proteins to be more like each other, a switch in their structure can occur. The approach involves creating a simplified sequence space to explore the mutational path and measure shifts in equilibrium between the folded and unfolded states.

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A minimal sequence code for switching protein structure and function

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  1. A minimal sequence code for switching protein structure and function Philip N. Bryan University of Maryland Biotechnology Institute, Rockville PNAS, October 12, 2009 Presented by Chao Wang

  2. Introduction • It is well known that the equilibrium between folded and unfolded can be radically shifted in either direction with a few mutations.

  3. Introduction • One begins with 2 stable proteins of similar size but different folds and mutates one to be more like the other until a switch in structure occurs. In practice this approach is not trivial, however. Any mutation in a protein will change the context of other amino acids. This is the essence of the folding problem. Our approach, therefore, was to create a simplified sequence space in which the mutational path from one fold to another can be explored and shifts in the equilibrium between the 2 folded states (and unfolded states) can be measured as a function of mutation. • Protein G • GA: 45, binding to human serum albumin • GB: 56, binding to Integrate Gene chips

  4. Methods

  5. Key mutants in the pathway

  6. Overall Change in Topology

  7. Hydrophobic Interactions

  8. Switching Mechanism

  9. Bypassing the Unfolded State • The persistence of order in mutants of low stability is consistent with basic principles: • (i) proteins collapse in water into compact structures; • (ii) compactness drives acquisition of secondary structure; and • (iii) final structural propensities are a subtle mix of many compensating weak forces.

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