Extending Iterative Protein Redesign and Optimization (IPRO) in protein library design for ligand specificity
Hossein Fazelinia 1, Patrick C. Cirino 1 and Costas D. Maranas 2*
1 Pennsylvania State University
2 Pennslyvania State University
* To whom correspondence should be addressed. E-mail: costas{at}psu.edu.
Submitted on August 28, 2006
Revised on November 7, 2006
Accepted on 6 December 2006
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Abstract |
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In this paper we are extending the IPRO (Iterative Protein Redesign and Optimization) (1) framework for the design of protein libraries with targeted ligand specificity. Mutations that minimize the binding energy with the desired ligand are identified. At the same time explicit constraints are introduced that maintain the binding energy for all decoy ligands above a threshold necessary for successful binding. The proposed framework is demonstrated by computationally altering the effector binding specificity of the bacterial transcriptional regulatory protein AraC, belonging to the AraC/XylS family of transcriptional regulators for different unnatural ligands. The obtained results demonstrate the importance of systematically suppressing the binding energy for competing ligands. By pinpointing a small set of mutations within the binding pocket, the difference in binding energies between targeted and decoy ligands, even when very similar, is greatly improved.
Key Words:
AraC, IPRO, changing effector specificity, computational protein design
