The Pocket Creator Objective

Protein receptors are often studied in a reduced form that concentrates on the ligand binding site and includes only residues that are at some distance from the ligand. Computing all the interaction energies between the atoms of a ligand and a full protein receptor is time consuming and most computations of protein-ligand interactions are truncated by some cutoff distance or by some reduction of the protein structure.

The large number of non-bonding interactions may thus focus on the most crucial ones. Cutoff distances are especially common if interactions have to be computed frequently, such as in molecular dynamics or in virtual docking. In docking of large databases, residues that align the ligand binding site or are close neighbors have a larger contribution to binding by electrostatic or Van der Waals interactions as well as by their surface interaction with the ligand, and it is unnecessary to include the full protein. However, truncating a protein to form a pocket around a ligand frequently creates partial chains and requires amendments to overcome structural problems due to spurious chain terminations and to short breaks in chains and in secondary structures (see images below).

Our script called Pocket Creator, tries to tackle that problem and creates binding pockets with minimal interference to the overall structure by adding small gaps and breaks to the cutoff structure (see script details below). With this web site, we provide the scientific community a web interface to the Pocket Creator script which saves and displays binding pockets that are useful for further research and computations.

The full structure of C-ABL Tyrosine Kinase(1OPK) with the ligand Myristic acid (orange). Pictures by Pymol

1OPK binding pocket done with a simple cutoff distance of 8Å from the ligand

1OPK binding pocket done with Pocket Creator. Gaps and breaks were added and the structure is mostly preserved

The Pocket Creator Applications

• Binding energy calculations
• Molecular dynamics calculations
• Docking calculations
• Virtual screenings
• Structural investigations
• Rational drug design

The Pocket Creator Script

Locating the ligand - As it reads the PDB file, it locates the ligand to which it relates as potential center for constructing a binding pocket. Any entity found in the protein file can be regarded as a ligand by the user, such as a water molecule or even a protein sequence
Saving residues in cutoff - Protein residues which have at least one atom at a user defined cutoff distance from each ligand’s atom are saved (8 Angstroms by default)
Minding the gap - Small gaps that are created due to the protein chain truncations are filled by the original residues in order to reduce the number of protein strands (maximum 3 residues by default)
Adding terminals - The script extends all non-natural backbone terminals to the alpha carbon of the adjacent residue, before the N-terminal of a partial chain and after its C-terminal, thereby keeping neutrality and the integrity of all peptide bonds

The Pocket Shapes

Induced - the pocket is selected by measuring the distance from each atom in the ligand to each atom in the complex, so that the pocket will be "induced" by the ligand's shape
Centered - the pocket is selected by measuring the distance from the geometric center of the ligand to each atom in the complex
Cavitary - the pocket is selected by measuring the distance from the cavity created in the binding pocket using the VOIDOO software, courtesy of Dr. Gerard J. Kleywegt from Uppsala University