Molecular Docking Server

Analysis of the mode of interaction between ligands and their target proteins is of crucial importance in order to explore different aspects of biochemical processes. Besides laboratory experiments, there is an emerging role of in-silico methods in investigating the interactions of ligands to proteins.

In-silico study of protein-ligand interaction involves molecular docking, where the binding energy and geometry of ligands, substrates or possible drug candidates to target proteins is predicted using computational chemistry methods.

The task in molecular docking assignments is to find the best ligand protein complex geometry. The problem is usually seen as an optimization task where the goal is to minimize the intermolecular interaction energy between the two molecules of interest. Since the possible number of ligand- protein complex geometry is usually very large, different algorithms are used in order to accurately explore the space of possible conformations while decreasing the computational power needed for the docking calculation at the same time.

Thus, a molecular docking calculation consists of the following steps:

(1) Optimization of the ligand geometry, calculate pH-dependent partial charges, identify rotatable bonds and

(2) Calculate electrostatic properties of the protein of interest and define the ligand-binding region,

(3) The ligand-protein interaction is then calculated by a scoring function that includes terms and equations that describe the intermolecular energies. The result of a docking calculation is a ligand-protein complex geometry and the corresponding binding energy. Therefore, for accurate interpretation of the results, a high-quality representation of the complex geometry is of great importance as well

(4)DockingServer integrates a number of computational chemistry software specifically aimed at correctly calculating parameters needed at different steps of the docking procedure, i.e. accurate ligand geometry optimization, energy minimization, charge calculation, docking calculation and protein-ligand complex representation.

Thus, the use of DockingServer allows the user to carry out highly efficient and robust docking calculation, which could not be achieved using single software so far. Since the calculations run on our servers, the use of DockingServer does not require powerful hardware or pre-installed software from the user.

The core of DockingServer web application is our integrating PHP software connected to a MySQL database, where the different tasks are automatically managed by daemons running on our servers and the input data will be read from the database and output data will be directed into the database.

The AutoGrid/AutoDock 4.0 (Morris, et al., 1998) program package is used for docking calculations, allowing docking of flexible ligands to proteins. With the help of Autodock program package the partial charges and atom types of the ligand and proteins can be assigned. However, the results of docking calculations strongly depend on the accuracy of charges calculated in the ligand.

Thus, besides offering ligand partial charge calculation with the Auto-Dock program package DockingServer also integrates calculator plug-ins from Chemaxon (Csizmadia, 2000) and the MOPAC2007 program (Stewart, 2007) for accurate pH-dependent protonation and ligand partial charge calculation. Moreover, geometry optimization, refinement of the ligand geometry using semiempirical methods (PM6) can be carried out. Automatic conversions between necessary file formats are achieved by Chemaxon tools.

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