ProBiS-CHARMMing: Web Interface for Prediction and Optimization of Ligands in Protein Binding Sites

Proteins
often exist only as apo structures (unligated) in the
Protein Data Bank, with their corresponding holo structures (with
ligands) unavailable. However, apoproteins may not represent the amino-acid
residue arrangement upon ligand binding well, which is especially
problematic for molecular docking. We developed the ProBiS-CHARMMing
web interface by connecting the ProBiS (http://probis.cmm.ki.si) and CHARMMing (http://www.charmming.org) web servers
into one functional unit that enables prediction of protein–ligand
complexes and allows for their geometry optimization and interaction
energy calculation. The ProBiS web server predicts ligands (small
compounds, proteins, nucleic acids, and single-atom ligands) that
may bind to a query protein. This is achieved by comparing its surface
structure against a nonredundant database of protein structures and
finding those that have binding sites similar to that of the query
protein. Existing ligands found in the similar binding sites are then
transposed to the query according to predictions from ProBiS. The
CHARMMing web server enables, among other things, minimization and
potential energy calculation for a wide variety of biomolecular systems,
and it is used here to optimize the geometry of the predicted protein–ligand
complex structures using the CHARMM force field and to calculate their
interaction energies with the corresponding query proteins. We show
how ProBiS-CHARMMing can be used to predict ligands and their poses
for a particular binding site, and minimize the predicted protein–ligand
complexes to obtain representations of holoproteins. The ProBiS-CHARMMing
web interface is freely available for academic users at http://probis.nih.gov.