This section of the users guide is intended to help a new user of dock get started with their first docking project. It describes the steps a user would typically take to apply the programs to a macromolecular target and potential ligands of interest. While the reference manual describes in detail the various input and output files, this guide is meant to convey the process in informal terms. Some of the difficulties we have encountered as well as approaches we have found useful are discussed.
dock is a program for locating feasible binding orientations, given the structures of a "ligand" molecule and a "receptor" molecule. What is considered feasible depends on how the orientations are evaluated. Current options are a contact (shape-fitting) score,a force field interaction energy and a new user-defined chemical scoring scheme. dock generates many orientations of one ligand. The best-scoring orientation of each molecule is saved, and the best-scoring molecules are written out. Some of the molecules in the list of best-scoring compounds, perhaps with modifications, may be interesting as potential new ligands for the receptor.
The basic requirement for docking is a structure of the macromolecule of interest. The docking procedure can be divided into four general stages: ligand preparation, site characterization, scoring grid calculation, and docking itself. Please refer to Figure 1 while reading this guide.
Site characterization is the process of deciding what areas of the receptor site to study. This is done by constructing site points to map out the negative image of the active site. These site points are used by dock to construct orientations of the ligand.
Scoring grid calculations are necessary so that dock can evaluate ligand orientations rapidly.
The final stage of the process is running dock and viewing the results. dock uses the site points to generate ligand orientations, then uses the precomputed grids to evaluate the orientations. The best-scoring molecules or orientations may be viewed using a molecular graphics program.
There are multiple tasks involved in the docking process, and each task can require many decisions over input parameters. We hope this beginner's guide will make it easier to navigate through the tasks and to select sensible parameters.
It is a good idea to make a make a new unix directory for each docking project using the unix mkdir command. Within this project directory make a sub-directory for each of the main tasks. Make a struc/ sub-directory to hold the ligand and receptor coordinates and molecular surfaces. Make a site/ sub-directory to hold the site point files. Make a grid/ sub-directory to hold the scoring grid files. Make a dock/ sub-directory to hold the dock files.
The output from some of the programs associated with dock, particularly MS, sphgen, and dock itself, may require substantial amounts of disk storage. Check before starting your job to make sure there is space available. It is a good idea to be cautious at first: use restrictive parameters choices with only a handful of ligands, to make sure that you are getting the results you desire. While dock jobs are running, check to be sure they are not creating overly large files.