Molecular Docking

	+		=
Protein Active Site		Ligand		Docking
Fig 1. Molecular Docking

Molecular docking is used to predict the structure of the intermolecular complex formed between two or more molecules. The most interesting case is the protein-ligand interaction, because of its applications to medicine. Ligand is a small molecule, which interacts with protein's binding sites. Binding sites are areas 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.

The most important application of docking software is virtual screening. In the screening, the most interesting and promising molecules are selected from an existing database. This places demands on the used computational method.

The search algorithm should create an optimum number of configurations that include the experimentally determined binding modes. These configurations are evaluated using scoring functions to distinguish the experimental binding modes from all other modes explored through the searching algorithm. A rigorous searching algorithm would go through all possible binding modes between the two molecules. However, this is impractical due to the size of the search space.

ViSION

ViSION is the initial letters of Virtual Screening & Investigation On Network.

Programming Aspects

This docking program is designed for @HOME network. All the sources were written in C#, a Microsoft .NET framework language. BMDL(Bioinformatics & Molecular Design Library), a molecular library, is designed to handle atomic or molecular objects. CsGL is used for a 3D graphical library of the viewer. And some component is mixed with GDI+.

Genetic Algorithms

Genetic algorithms use ideas based on the language of natural genetics and biological evolution. In the case of molecular docking, the particular arrangement of a ligand and a protein can be defined by a set of values describing the translation and orientation of the ligand with respect to the protein: these are the ligand's state variables and, in the GA, each state variable corresponds to a gene. The ligand's state corresponds to the genotype, whereas its atomic coordinates corresponds to the phenotype. In molecular docking, the fitness is the total interaction energy of the ligand with the protein, and is evaluated using the energy function.

ForceField Based Scoring Function

Current structure-based scoring functions seek to remedy some of the deficiencies of traditional force fields by developing empirical free energy functions that reproduce observed binding constants. Most of these approaches use an expanded "master equation" to model the free energy of binding, adding entropic terms to the molecular mechanics equations.

In the development of an forcefield based free energy function, the desolvation term was most challenging, because Vision uses a grid-based method for energy evaluation, and most published solvation methods are based on surface area calculations. We investigated HFED method of calculating the desolvation energy.