Molecular simulations with solvent competition quantify water displaceability and provide accurate interaction maps of protein binding sites

J Med Chem. 2014 Oct 23;57(20):8530-9. doi: 10.1021/jm5010418. Epub 2014 Oct 14.


Binding sites present well-defined interaction patterns that putative ligands must meet. Knowing them is essential to guide structure-based drug discovery projects. However, complex aspects of molecular recognition-such as protein flexibility or the effect of aqueous solvation-hinder accurate predictions. This is particularly true for polar contacts, which are heavily influenced by the local environment and the behavior of discrete water molecules. Here we present and validate MDmix (Molecular Dynamics simulations with mixed solvents) as a method that provides much more accurate interaction maps than ordinary potentials (e.g., GRID). Additionally, MDmix also affords water displaceability predictions, with advantages over methods that use pure water as solvent (e.g., inhomogeneous fluid solvation theory). With current MD software and hardware solutions, predictions can be obtained in a matter of hours and visualized in a very intuitive manner. Thus, MDmix is an ideal complement in everyday structure-based drug discovery projects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • HIV Protease / chemistry
  • HIV Protease / metabolism
  • HSP90 Heat-Shock Proteins / chemistry
  • HSP90 Heat-Shock Proteins / metabolism
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Reproducibility of Results
  • Software*
  • Solvents / chemistry
  • Water


  • HSP90 Heat-Shock Proteins
  • Proteins
  • Solvents
  • Water
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1