GRID manual
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Chapter 3. General introduction

This User Manual applies to six main Programmes called GREATER, GREAT, GRIN, GRID, , GVIEW and to one datafile called GRUB, and to the GRID-based docking programme GLUE. It is a reference manual. Experienced and new Users should study the Tutorials sections.

This manual replaces all previous editions, and should only be used in conjunction with Version 22 of the Molecular Discovery Programmes.

The Molecular Discovery Programmes are used in order to predict specific noncovalent interactions between a molecule of known three dimensional structure (the "Target"), and a small chemical group (the "Probe") whose properties are defined by the User. A wide range of Targets may be studied including enzymes, nucleic acids, poly-saccharides, glycoproteins, peptides, membranes, crystals, drug molecules, photographic materials, dyestuffs and many other organic chemicals. Many Targets can be studied one after the other in a single Grid run, and they are called a "Set" of Targets.

GRID is the main Programme, and the overall GRID method was first described in the Journal of Medicinal Chemistry. (1985). Volume 28. Pages 849-857. The Programmes have been rewritten and greatly extended since that paper was submitted for publication, but the original reference still provides a good introduction to the general method. The individual Programmes will now be briefly described.

3.1. Overview of programme GREATER

GREATER is a Graphical User Interface (GUI) for the GRID package of Programmes. It provides GUI access to most of the functionality of Programmes GRIN and GRID and also to Programme GREAT which was the predecessor of GREATER. Furthermore the interactive Graphical User Interface of GREATER is closely integrated with GVIEW, and this helps the user to visualise the structure of the Target and the results of the GRID computation simultaneously.

In fact GREATER is a sophisticated "wrapper" for the suite of GRID Programmes, and it works in two integrated stages. First the necessary command files are produced for GRIN and/or GRID, and then the Programmes are started and run in the correct sequence. Thus a job under the control of GREATER uses exactly the same programmes and data as an experienced User would use when setting up the jobs manually, and the Programmes are at all times directly accessible in command mode. The whole process under GREATER is fully transparent to the User who can import target structures, compute the Molecular Interaction Fields (MIFs) and view or export the results within the interactive graphical interface.

New Users, and other scientists who have not used GRID recently, may find it particularly helpful. If you want to know more about Greater please refer to Chapter 46.

3.2. Overview of programme GREAT

Programme GREAT is the standard programme to supervise the Molecular Discovery Programmes. It is a menu-driven Programme which first prepares the necessary files, and then initiates runs with the Molecular Discovery Programmes. New Users, and other scientists who have not used GRID recently, may find it particularly helpful.

3.2.1. Preparation of input files

As mentioned above, there are several alternative formats which might have been used for the original xyz coordinates of the Target. Furthermore, the same atom in the same molecule might have been given various different names by different workers. For instance the carbon atoms of propane might be called:

C1  C2  C3                  or:
CA  CB  CG                  or:
Calpha  Cbeta  Cgamma       or:
C(I)  C(II)  C(III)

Programme GREAT can read a wide range of xyz formats, and can deal with many different systems of atom names. After various checks it prepares a file in standard PDB format, which can be used as input for Programme GRIN or for many other programs. It can process a whole Set of Targets one after the other in a single GREAT run.

If you want to know more about GREAT please refer to Chapter 4.

3.3. Overview of programme GRIN

Programme GRIN is used in order to prepare the input for the main Programme GRID. GRIN must therefore be used before GRID. The primary input for GRIN is the xyz positions of the atoms in the Target molecule. These coordinates must be provided by the User in the internationally recognised format specified for the Protein Data Bank at Brookhaven. An input file containing these coordinates is known as a PDB file (Figure 1). GRIN can accept several different PDB files each containing one Target, and deal with them automatically one after the other as a "Set".

Several other formats for the xyz coordinates of atoms are in common use. Another Programme (GREAT) can read many of these formats and convert them into the PDB format which is required by Programme GRIN. It can deal with a whole Set of Targets one after the other. The secondary input for GRIN is a set of "Energy Variables" which are contained in a datafile called GRUB. These Energy Variables must be correctly specified for every atom in the Target molecule, in order to define how the Target will interact with the Probe. The general relationships between files and Programmes are shown in diagram 1 below. The main function of Programme GRIN is to check the PDB and GRUB files, and merge them so that appropriate Energy Variables are specified for each atom in the Target. When this has been done correctly, an output file (GRINKOUT = GRIN Koordinate OUTput) is produced. This GRINKOUT file is a list of Target atoms in the correct sequence with their x, y, z coordinates and Energy Variables. It is used as checked input for the main Programme GRID.

If you want to know more about Grin please refer to Chapter 5.

3.3.1. Diagram 1: simplified flow chart for the programmes

(A more detailed flow chart is shown in Figure 2)

3.4. Overview of programme GRID

The GRID User takes GRINKOUT as an input file which defines the properties of the Target. However, it is still necessary to decide on the chemical properties of the Probe. For example an alkyl hydroxy Probe has a certain Van der Waals radius; a certain electro- static charge; makes hydrogen bonds of a certain strength; can approach rather closer to another hydrogen-bonding atom than the two Van der Waals radii would suggest; and can donate one and accept two hydrogen bonds with sp³ geometry. This information is supplied to Programme GRID which then computes the places on the Target at which the Probe would interact favourably. Several Probes, each with different properties, may be used one after the other. GRID can accept several different GRINKOUT files each containing one Target, and deal with them automatically one after the other as a "Set".

Note on probe types: There are four distinct classes of Probe. The largest class are traditional Grid Probes containing one heavy atom and the appropriate number of hydrogens (eg: the hydroxy oxygen Probe just described). Multi-atom Probes have more than one heavy atom, and include carboxy groups, amidine and amides. Entire molecules are used by Programme GLUE as Multi-Probes entities.

Targets are by default considered as rigid molecules with tautomeric hydrogens, and different conformations of the Target may be studied one after the other. Alternatively the Target may be subdivided into a rigid "Core" region with conformationally flexible side-chains. In this case the flexible side-chains alter their conformation appropriately as they interact with the Probe.

The results from GRID can be used as the input for further computations, and are also provided in tabular form. The User will normally study several different Probes (eg: hydroxyl oxygen, carbonyl oxygen, carboxy oxygen, amino nitrogen, amido nitrogen, etc) acting on the same Target or Set of Targets, and the collated results can then be used in order to design novel molecules or to make other predictions.

If you want to know more about GRID please refer to Chapter 26.

3.5. Overview of programme GVIEW

The results from GRID can be displayed by programme GVIEW or by other computer graphics if appropriate hardware and software are available. Gview is the application used from version 19 of GRID to visualise Molecular Interaction Fields, GRID energy contributions due to atoms of the Target, and (macro)molecular structures with distances, torsional and dihedral angles. The application can be also used to export the data to standard formats (Sybyl, Insight, Inventor) and to print or save the images in Postscript or RGB format.

The simplest and fastest way to import molecules into Gview is to use "drag and drop". Gview recognises the format of the molecular structure by the extension of the file. If you want to know more about Gview please refer to Chapter 45.

3.6. Overview of programme GLUE

Programme GLUE detects selective binding sites on a Target molecule of known structure. It is a GRID-docking programme used to find possible interaction sites for a small rigid molecule with another molecule (the "Target"). GLUE requires, as input, only the two 3D structures of the ligand-Target molecules. The procedure benefits of a graphical interface which helps in preparing the Target and allows to visualise the docking of the ligand molecule within the protein cavity.

If you want to know more about GLUE please refer to Chapter 41.

3.7. Overview of utility programmes

About a dozen Utility Programmes are provided. They are described near the end of this User Manual, and are mostly used to manipulate files or change their formats.

If you want to know more about Utility programmes please refer to Chapter 43.

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