Protein-ligand interface

Zhang, S., Golbraikh, A., Tropsha, A. (2006) Development of quantitative structurebinding affinity relationship models based on novel geometrical chemical descriptors of the protein-ligand interfaces. JMed Chem 49, 2713-2724. 

Structure-based Chemical Descriptors of Protein-Ligand Interface The EnTESS Method... 

Since we employed the concept of electronegativity combined with Delaunay tciiellation of protein-ligand complexes we termed these unique characteristics of the protein-ligand interface the EnTess descriptors We have applied the variable selection A -nearest neighbor (A NN) QSAR approach to establish correlations between binding affinities and the EnTess descriptors as described below. 

Panigrahi SK, Desirajn GR. Strong and weak hydrogen bonds in the protein-ligand interface. Proteins 2007 67 128-141. 

Good steric complementarity also implies that there are no cavities along the protein-ligand interface. LUDI can detect and measure cavities along the protein-ligand interface. It is possible to specify a upper limit for the cavity volume in the selection step. 

There are three water molecules at the protein-ligand interface (shown as spheres), which are preserved across all crystal structures. There are only minor movements of these water molecules, mostly within experimental error and to accommodate the binding of ligands. 

There are two water molecules at the protein-ligand interface (shown as darker coloured spheres in Fig. 8b, h and i), which are present in the apo structure and some structures with fragments, but which are displaced in other structures. 

Fig. 8 Detail of the crystal structures of the Nt-Hsp90 active site (see legend to Fig. lc) and selected solvent molecules and ligands in crystal structures of various individual fragments (a-c, e) a double fragment soak (d) the initial lead compound (g) that led to AUY922 (f) apo Nt-Hsp90 (h) and PU3 (i). Circles indicate the two positions of L107 spheres indicate water molecules at the protein-ligand interface. See text for details...

Burgoyne MJ, Jackson RM (2006) Predicting protein interaction sites binding hot-spots in protein-protein and protein-ligand interfaces. Bioinformatics 22 1335-1342... 

A number of more general issues, associated with the selection and preparation of a receptor structure, should be noted. In particular for crystal structures, water molecules and ions present at the protein-ligand interface can pose serious problems for identifying or optimizing lead compounds. In many cases, it is difficult to predict whether a water molecule or ion can be replaced. Ions are especially difficult to treat computationally since their formal charge and the associated desolvation energy are often difficult to model. Their inclusion - or exclusion - is arguable. 

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