Molecular Recognition: An Example from Ligand Binding to Proteins

  • M. Karplus
  • F. T. K. Lau
Part of the NATO ASI Series book series (ASIC, volume 426)


To illustrate the use of free energy simulations for increasing our understanding of molecular recognition, alchemical molecular dynamics simulations are performed to evaluate the interactions involved in determining the difference in the free energy of binding of the tyrosine substrate between the wild type of tyrosyl-tRNAsynthetase (TyrRS) from Bacillus stearothermophilus and the mutant Tyr 169 → Phe. The Tyr 169 hydroxyl group interacts with the ammonium group of the substrate in a manner corresponding to that found in other amino acid binding proteins (e.g., the Asp receptor of the chemotactic bacterium Salmonella typhimurium (Milburn et al., 1991) and class I major histocompatibility complex molecules (Madden et al., 1992)). The calculated free energy change due to the Tyr 169 → Phe mutation is 3.4 kcal/mol (the statistical error is ±0.5 kcaVmol) in satisfactory agreement with the experimental value of 3 ± 0.5 kcal/mole. By use of thermodynamic integration, the contribution of the different terms to the free energy change are estimated. It is found that there are large protein contributions to the alchemical free energy difference of the bound and free enzyme but that they cancel in the overall result. Due to this cancellation, the essential interactions contributing to the free energy change are those between the OH group of Tyr 169 and water in the free enzyme and those between the OH group of Tyr 169 and the ammonium group of the substrate in the bound system. The results support simple models based on a balance of hydrogen bonding interactions (Jencks, 1969; Hine, 1972; Fersht, 1988).


Free Energy Free Energy Change Free Enzyme Ammonium Group Potential Energy Function 
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Copyright information

© Springer Science+Business Media Dordrecht 1994

Authors and Affiliations

  • M. Karplus
    • 1
  • F. T. K. Lau
    • 1
  1. 1.Department of Chemistry HarvardUniversity CambridgeMassachusettsUSA

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