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Related Experiment Videos

Conformational changes of small molecules binding to proteins

M C Nicklaus1, S Wang, J S Driscoll

  • 1Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Bioorganic & Medicinal Chemistry
|April 1, 1995
PubMed
Summary

Flexible molecules alter their shape when binding to proteins. Analysis reveals protein-bound conformations differ from crystal structures and energy minimums, impacting drug design strategies.

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Area of Science:

  • Molecular biology
  • Structural biology
  • Computational chemistry

Background:

  • Flexible molecules undergo conformational changes upon protein binding.
  • Understanding these changes is crucial for molecular recognition and drug design.

Purpose of the Study:

  • To investigate the conformational changes of flexible molecules upon protein binding.
  • To compare protein-bound conformations with crystal structures and calculated energy minimums.
  • To assess the energetic landscape of these conformations.

Main Methods:

  • Analysis of 33 compounds with available crystal and protein-bound structures from the Cambridge Structural Database and Brookhaven Protein Data Bank.
  • Molecular mechanics calculations using CHARMm to determine global energy minimum conformations.

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  • Semi-empirical calculations (AM1, PM3) to confirm conformational energies.

    • Main Results:

    • Protein-bound conformations consistently differ from both crystal structures and global energy minimums.
    • The extent of conformational deformation correlates with the number of rotatable bonds in the molecule.
    • Most analyzed conformations (crystal and protein-bound) are energetically unfavorable, lying above local or global energy minima.

    Conclusions:

    • Flexible molecules adopt non-ideal conformations when binding to proteins, deviating significantly from their lowest energy states.
    • These findings highlight limitations in predicting bound conformations based solely on energy minimization.
    • The study suggests a need for advanced computational approaches in drug design to account for significant conformational flexibility and energetic penalties.