Mr.Halavath Ramesh 16-MCH-001 Dept. of Chemistry Loyola College University of Madras-Chennai.

Introduction The three dimensional structure known may be represented to show different views of the structures with complex molecular mechanics programs it is possible to super impose one structure on another. The same approach is used to super impose the three dimensional structure of a potential drug on its possible target site. This process which is often automated is known as docking. Molecular docking is used to predict the structure of the inter molecular complex formed between two molecules. The small molecules are called Ligands usually interact with proteins binding sites. Binding sites are of protein Known to be active in forming of compounds. There are several possible mutual conformations in which binding may occur. These are commonly called Binding modes. Its also predict the strength of the binding,the energy of the complex, the type of signal produced and calculate the binding affinity between two molecules using scoring functions. The most interesting case is the type protein-Ligand interaction, which has its applications in medicine.

Docking Glossary Molecular Docking : Means Optimization problem,which would describe the “ Best –Fit” orientation of a Ligand that binds to a particular protein of interest. However, Since both the Ligand and the protein are flexible “ a hand –in-glove” analogy is more appropriate than “ Lock and Key”. Molecular docking is the process that involves placing molecules in appropriate configurations to interact with a receptor. Molecular Docking is a natural process which occurs within seconds in a cell. Receptor or Host or Lock: The “ receiving” molecule most commonly a protein or other biopolymers. Ligand or Guest or Key: The Complementary partner molecule which binds to the receptor. Ligands are most often small molecules but could also be another biopolymer. Docking: Computational simulation of a candidate Ligand binding to a receptor. Binding Mode: The orientation of the Ligand relative to the receptor as well as the conformation of the of the Ligand and receptor when bound to each other. Pose: A Candidate binding mode. Scoring: The process of evaluating a particular pose by counting the number of favorable inter molecular interaction such as hydrogen bonds and hydrophobic contacts. Ranking: The process of classifying which ligands are most likely to interact favorably to a particular receptor based on the predicted free-energy of binding.

Different type of interaction It is very common to define the interaction between particles to be the consequence of forces between the molecules contained by the parcticles.Often forces are divided into four categories: 1.Electrostatic Forces 2. Electrodynamics Forces 3. Steric Forces 4. solvent-related Forces 1.Electrostatic Forces: Forces with electrostatic origin are due to the changes residing in the matter. The most common interactions are charge-charge, charge-dipole and dipole-dipole. 2.Electrodynamic Forces: The most widely known is probably the van der Waals interaction. 3.Steric Forces: Steric forces are caused by entropy. For example, in cases where entropy is limited, there may be forces to minimize the free energy of the system, which are due to entropy. 4.Solvent-related Forces: Solvent-related forces are due to the structural changes of the solvent. These structural changes are generated, when ions, colloids, proteins etc, are added into the structure of solvent. The most commonly are Hydrogen bond and hydrophobic interactions.

Molecular docking Molecular docking can be divided into two separate sections. 1)Search algorithm – The algorithm should create an optimum number of configurations that include the experimentally determined binding modes. 2)Scoring Function- – These are mathematical methods used to predict the strength of the noncovalent interaction called as binding affinity, between two molecules after they have been docked. Scoring functions have also been developed to predict the strength of other types of intermolecular interactions, for example between two proteins or between protein and DNA or protein and drug. These configurations are evaluated using scoring functions to distinguish the experimental binding modes from all other modes explored through the searching algorithm.

Pocket Defining the Pocket: ** Known interaction sites. ** Explore the protein surface. ** Multiple alignment -- Conserved hydrophobic on the surface. -- Patches of conserved residues. *** Identify Cavities. *** Usually the largest pocket is the binding site. Docking Approaches: 1.Shape Complementary: One approach uses a matching techniques that describe the protein and the Ligand complementary surface. 2.Simulations: MD(Molecular Dynamics) is a computer simulation method for studying the physical movements of atoms and molecules. Forces between potential energies.

Molecular Docking Procedure 1. Receptor Building-The receptor is down loaded from RCSB PDB. 2.After down loading the PDB format of the protein remove the water molecules by editing the TEXT of the protein. 3.Optimizing the protein by the parameters available in the software. Upload the pdb file and select the GA parameter likes population size, generations etc which are necessary for docking accuracy. Prepare the binding site using the same panel displayed.Set the output path to store the prepared structure. 4.The active site is predicted and later the Ligand is uploaded. Arrange all the parameter such as number of pose to be obtained and score and start the docking. 5.The scoring is calculated and even the fitness is displayed,analyzed your data and select the most optimum Ligand and its pose. 6. iGEM Dock-----Software 7.The complex can be viewed and checked for the orientation of the Ligand with receptor. 8.Various formats are available for representation and analyzing. 9. The ball and stick view.

Vander Waals Interaction Vander Waals forces are driven by induced electrical interaction between two or more atoms or molecules that are very close to each other. Vander Waals interaction is the weakest of all inter molecular attractions between molecules.vander Waals interaction is the another important bonding type that helps stabilizing the protein structure. In the coiled-coil protein there is a interaction between side chain in alpha helix. If these repeating residues are hydrophobic such as leucine,Vander Waals interaction will be formed to stabilize this protein structure. The Vander Waals interaction is occurs by the symmetrical distribution and unsymmetrical distribution of electrons,nucleus. London Dispersion forces: The London dispersion forces is the weakest inter molecular force. The London dispersion force is a temporary attractive force that results when the electrons in two adjacent atoms occupy positions that make the atoms form temporary dipoles. This forces is some times called in induced dipole-induced dipole attraction. Scaffold Protein Interaction: In biology Scaffold protein are crucial regulators of many key signaling path ways. Its forms interactions and or bind with multiple members of a signaling path ways, to specific areas such as plasma membrane,cytoplasma, nucleus, Golgi endo somes, and Mitochondria.