Improved Physics-Based Single-Position Protein Sequence Redesign with a Residue-Pairwise Generalized Born Model
1Laboratoire de Biologie Structurale de la Cellule (CNRS UMR7654), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France.
The Journal of Physical Chemistry. B
|October 7, 2025
Summary
Computational protein design (CPD) advances by improving energy functions. This study extends the fluctuating dielectric boundary (FDB) approach for more accurate solvation models, enhancing protein sequence design.
Area of Science:
- Computational biology
- Biophysics
- Protein engineering
Background:
- Computational protein design (CPD) seeks to create novel proteins with desired functions.
- Accurate energy functions are crucial for discriminating protein sequences and conformations.
- Existing methods often use pairwise approximations for solvation, limiting accuracy.
Purpose of the Study:
- To extend the fluctuating dielectric boundary (FDB) approach for generalized Born (GB) solvation to entire proteins.
- To apply the improved FDB-GB model to single-position protein sequence redesign.
- To enhance the realism of electrostatic models in CPD software.
Main Methods:
- Implementation of the FDB approach for exact GB term decomposition in the Proteus software.
- Application of the enhanced model to single-position redesign of protein sequences.
- Utilizing a physics-based energy function combining molecular mechanics (MM) and GB solvation.
Main Results:
- A notable improvement in the quality of designed protein sequences was achieved.
- The extended FDB-GB approach provides a more accurate electrostatic model for CPD.
- The Proteus software now features one of the most realistic electrostatic models among CPD tools.
Conclusions:
- Extending the FDB approach to the whole protein significantly improves sequence design quality.
- The enhanced Proteus software offers a more realistic electrostatic modeling capability for computational protein design.
- This work advances CPD by providing a more accurate and transferable energy function.
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