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Probing the mutational interplay between primary and promiscuous protein functions: a computational-experimental
Hector Garcia-Seisdedos1, Beatriz Ibarra-Molero, Jose M Sanchez-Ruiz
1Facultad de Ciencias, Departamento de Quimica Fisica, Universidad de Granada, Granada, Spain.
Plos Computational Biology
|June 22, 2012
Summary
Protein evolution can enhance both primary and new promiscuous functions simultaneously. This study explores natural evolution
Area of Science:
- Protein Engineering and Molecular Evolution
- Biochemistry and Biophysics
Background:
- Protein promiscuity is key to metabolic plasticity, molecular evolution, and biotechnology.
- Existing research often focuses on laboratory evolution to enhance promiscuous activities.
- The natural evolutionary pathways for simultaneous modulation of primary and promiscuous functions are less understood.
Purpose of the Study:
- To investigate the simultaneous modulation of primary and promiscuous protein functions during natural evolution.
- To develop a computational/experimental approach for analyzing evolutionary patterns of protein activity.
- To explore the engineering of multi-functional enzymes through directed evolution.
Main Methods:
- Utilized function-targeted statistical coupling analysis on evolutionary data to identify key mutation sites.
- Created and screened combinatorial libraries for both primary and promiscuous activities.
- Employed partial-least-squares reconstruction to model the full combinatorial space and derived Pareto sets for optimal activity combinations.
Main Results:
- Revealed diverse patterns of primary and promiscuous activity modulation during natural evolution.
- Observed a scenario with simultaneous moderate enhancement of both primary and promiscuous activities in thioredoxin scaffolds.
- The conformational diversity hypothesis provides a simple explanation for the observed evolutionary patterns.
Conclusions:
- Natural evolution can lead to simultaneous enhancement of primary and promiscuous protein functions.
- The developed computational approach aids in understanding protein evolution and designing multi-functional enzymes.
- This method offers a basis for efficient directed evolution protocols targeting multiple protein features.
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