Exploring the energy landscapes of molecular recognition by a genetic algorithm: Analysis of the requirements for robust docking of HIV-1 protease and FKBP-12 complexes
✍ Scribed by Gennady M. Verkhivker; Paul A. Rejto; Daniel K. Gehlhaar; Stephan T. Freer
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 1011 KB
- Volume
- 25
- Category
- Article
- ISSN
- 0887-3585
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✦ Synopsis
Energy landscapes of molecular recognition are explored by performing "semi-rigid" docking of FK-506 and rapamycin with the Fukisawa binding protein (FKBP-121, and flexible docking simulations of the Ro-31-8959 and AG-1284 inhibitors with HIV-1 protease by a genetic algorithm. The requirements of a molecular recognition model to meet thermodynamic and kinetic criteria of ligand-protein docking simultaneously are investigated using a family of simple molecular recognition energy functions. The critical factor that determines the success rate in predicting the structure of ligand-protein complexes is found to be the roughness of the binding energy landscape, in accordance with a minimal frustration principle. The results suggest that further progress in structure prediction of ligand-protein complexes can be achieved by designing molecular recognition energy functions that generate binding landscapes with reduced frustration.