Protein Conformational Flexibility Modulates Kinetics and Thermodynamics of Drug Binding

Nat Commun. 2017 Dec 22;8(1):2276. doi: 10.1038/s41467-017-02258-w.


Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Drug Design*
  • Entropy
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Kinetics
  • Ligands*
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Protein Binding / physiology*
  • Protein Conformation*
  • Surface Plasmon Resonance
  • Thermodynamics*


  • HSP90 Heat-Shock Proteins
  • Ligands