title: Prediction of water and metal binding sites and their affinities by using the Fold-X force field.
abstract: The empirical force field Fold-X was developed previously to allow rapid free energy calculations in proteins. Here, we present an enhanced version of the force field allowing prediction of the position of structural water molecules and metal ions, together called single atom ligands. Fold-X picks up 76% of water molecules found to interact with two or more polar atoms of proteins in high-resolution crystal structures and predicts their position to within 0.8 A on average. The prediction of metal ion-binding sites have success rates between 90% and 97% depending on the metal, with an overall standard deviation on the position of binding of 0.3-0.6 A. The following metals were included in the force field: Mg2+, Ca2+, Zn2+, Mn2+, and Cu2+. As a result, the current version of Fold-X can accurately decorate a protein structure with biologically important ions and water molecules. Additionally, the free energy of binding of Ca2+ and Zn2+ (i.e., the natural logarithm of the dissociation constant) and its dependence on ionic strength correlate reasonably well with the experimental data available in the literature, allowing one to discriminate between high- and low-affinity binding sites. Importantly, the accuracy of the energy prediction presented here is sufficient to efficiently discriminate between Mg2+, Ca2+, and Zn2+ binding.
authors: European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg D-69117, Germany.
authors: Joost W H
authors: JW
authors: Schymkowitz
authors: Frederic
authors: F
authors: Rousseau
authors: Ivo C
authors: IC
authors: Martins
authors: Jesper
authors: J
authors: Ferkinghoff-Borg
authors: Francois
authors: F
authors: Stricher
authors: Luis
authors: L
authors: Serrano
mesh_terms: D001703:Biophysics / Q000379:methods*; D002623:Chemistry Techniques, Analytical / Q000379:methods*; D019216:Metals, Heavy / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D017510:Protein Folding; D014867:Water / Q000737:chemistry*
chemical_list: D019216:Metals, Heavy; D014867:Water