Computer Simulation of Protein-Ligand Interactions

Challenges and Applications
  • Sergio A. Hassan
  • Luis Gracia
  • Geetha Vasudevan
  • Peter J. Steinbach
Part of the Methods in Molecular Biology™ book series (MIMB, volume 305)


The accurate modeling of protein-ligand interactions, like any prediction of macromolecular structure, requires an energy function of sufficient detail to account for all relevant interactions and a conformational search method that can reliably find the energetically favorable conformations of a heterogeneous system. Both of these prerequisites represent daunting challenges. Consequently, the routine docking of small molecules or peptides to proteins in their correct binding modes, and the reliable ranking of binding affinities remain unsolved problems. Nonetheless, computational techniques are continually evolving so as to broaden the range of feasible applications, and the accuracy of predictions and theoretical approaches can often be of great help in guiding and interpreting experiments. We discuss the energetics of protein-ligand systems and survey conformational searching techniques. We illustrate how molecular modeling of a protein-ligand complex sheds light on the observed resistance of a mutant dihydrofolate reductase to the antibiotic trimethoprim. In another example, we show that relaxation of side chains in different crystal structures of the same complex, benzamidine bound to trypsin, is needed to draw sensible conclusions from the calculations. The results of these relatively simple conformational searches underscore the importance of incorporating protein flexibility in simulations of protein-ligand interactions, even in the context of relatively rigid binding pockets.

Key Words

Molecular mechanics molecular dynamics Monte Carlo simulation conformational searching protein-ligand interaction implicit solvent free energy binding affinity 


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Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Sergio A. Hassan
    • 1
  • Luis Gracia
    • 2
  • Geetha Vasudevan
    • 3
  • Peter J. Steinbach
    • 1
  1. 1.Center for Molecular Modeling, Division of Computational Bioscience, Center for Information TechnologyNational Institutes of HealthBethesda
  2. 2.Department of Physiology and Biophysics, Weill Medical CollegeCornell UniversityNew York
  3. 3.Scientific Computing, Medarex Inc.Sunnyvale

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