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Folding free energy function selects native-like protein sequences in the core but not on the surface
Alfonso Jaramillo1, Lorenz Wernisch, Stéphanie Héry
1Unité de Conformation de Macromolécules Biologiques, CP160/16, Université Libre de Bruxelles, 50 Avenue F. D. Roosevelt, 1050 Brussels, Belgium.
Summary
This study designed new protein sequences using only backbone structures and physical principles. Designed sequences matched natural proteins in the core but differed on the surface, aiding protein fold recognition.
Area of Science:
- Computational biology
- Protein engineering
- Structural bioinformatics
Background:
- Protein sequences dictate structure and function.
- Predicting native-like sequences from structure is challenging.
- Current methods often require native sequence information.
Purpose of the Study:
- To develop an automatic protein design procedure.
- To optimize folding free energy for given protein structures.
- To compare designed sequences with natural counterparts.
Main Methods:
- Utilized known protein backbone structures and a rotamer library.
- Employed a classical empirical force field based on physical principles.
- Applied the design procedure to 7 protein folds (45 native structures).
Main Results:
- Designed sequences showed high similarity to native sequences in the protein core.
- Designed sequences differed significantly from native sequences on the protein surface.
- Designed and natural sequences scored higher than random sequences against derived profiles.
- Designed sequence profiles enabled retrieval of native sequences via PSI-BLAST.
Conclusions:
- The design procedure successfully generates plausible protein sequences.
- Differences between designed and native sequences highlight evolutionary selection pressures.
- Findings advance understanding of protein sequence-structure relationships.
- This approach shows promise for improving protein fold recognition and design.