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Chapter 1. GRID22 - Changes from previous editions
This page indicates where there are important alterations from Version 21 User Manual. The new features are fully documented and hyper-linked in the new User Manual and are just briefly explained here.
1.1. The GLUE docking programme
GLUE is a docking programme using all the GRID force fields options and capabilities. GLUE fits ligands molecules into a set of GRID maps of a target structure. The input target structure (protein) must be prepared for the Target as usual, but GREATER interface can make this work much more simpler. Moreover, the subsequent generation of a set of GRID maps on that Target has been automated. GLUE is able to carry out the various steps needed to obtain one or more docked positions of the ligand into the target in automatic way. Programme GLUE would now require only two input files: the target protein in the kout format, and the ligand molecule(s) to dock into the protein. Optionally the User may provide the location of the docking by using a simple grid cage in ASCII format. GLUE will then generate the GRID maps for the probes that are going to simulate at best the ligand structure. The GRID maps can be further elaborated using a graphical editor, and chemical features used to bias the docking results in virtual screening. FLAP results (Fingerprint for Ligands And Proteins) can be used as input for the docking software, with a general improves of the docking performances. Finally, GLUE saves the results of the docking in a single file for graphical analysis. This sort of information can be of particular value for ligand design, because a small structural alteration of the ligand(s) might be made in order to favour one of the binding modes at the expense of the others. Programme GLUE represents the last evolution of the docking programme GROUP (present since version 19). GROUP and AUTOGROUP programmes have been discontinued, since all their options and capabilities are now inserted in GLUE. GLUE runs in UNIX and LINUX systems.
1.2. The WINDOWS support has been started
After long tests we are pleased to announce that the Windows operating system will be supported by the new release of GRID. The Windows version of GRID is now available for distribution to the User with a regular GRID license term for one year-free period of time.
1.3. Advanced MIF viewer
The graphic module of GRID, called Gview, is used to display all the resulting GRID force fields in all the operating systems. GVIEW is a stand-alone application that uses sophisticated input-output techniques such as the drag and drop import to help the User in the graphic visualisation of the MIF and the (macro)molecular structures. Gview has been improved introducing new features in order to make it more flexible and powerful. Torsional-angles, distance between atom-pairs or atom and grid nodes can be evaluated and reported in the 3D graphic plots. A secondary representation of the macromolecular structure can be easily reported and coloured. The protein residues are labelled with different options in the graphic window. Gview now supports multiple field levels, together with multiple surfaces rendering, at the same time. The colour selector for MIF has been improved.
1.4. IHAC directive (controls the method for charge distribution)
From this version 22 the GRIN output can be controlled by a new directive IHAC. The default value is IHAC=0.0 and this leaves the output as it was in the previous release. The output is also unchanged if IHAC is omitted altogether from the command file. When IHAC is set to the alternative value 1.0 GRIN uses a semiempirical method to compute the charge distribution in a molecule or a list of molecules. The new charges are then written by GRIN to the .KOUT output file, and the subsequent operations remain unchanged. The new charges show little effect on the strongest energy values and pattern of the Molecular Interaction Field. However, a larger effect can be observed when the MIF contours are studied at medium or small energy threshold values.
1.5. The number of single-atom Grid probes has been increased from 56 to 64
New GRID single-atom probes has been fully integrated in GRID force field after a careful parameterisation, when necessary. These probes are now available in all the GRID computation, from the general probe-target interaction, to the docking process. The new Probes include: thiophen or thioether sulphur, aromatic-O-aliphatic ether oxygen, aromatic-O-aromatic ether oxygen, sp2 nitrogen with 2 LP and 1 double bond, oxygen of sulphones, pyramidal sulphur of sulphoxide, fluorine of CF2 -CF3 groups, sulphone-bonded fluorine.
1.6. New values for KWIK directive
KWIK can be used to alter the speed or size of the GRID computation. The alteration is made with the purpose to retain the information, with a significant increase of the speed of the calculation. Its default value is zero, and KWIK then has no effect. In a normal Grid run with a single Target KWIK can be set to 5, 6 or 7 with the following results: KWIK=5 is optimal for small ligand. When KWIK=5 the energy values for the omitted grid points are set to zero. Only the grid points lying in the corners of the box, where they are far from the Target molecule are set to zero. This makes the Programme run more quickly (two or three time faster). KWIK=6 is optimal for macromolecules. KWIK=6 include the KWIK=5 option, but when KWIK=6 further grid points are omitted from the computation. The points are those located inside of the macromolecule, where there is no space for the probe. To these points the GRID energy cut-off is set to +5 kcal. The value KWIK=5 & 6 can be used if one are studying several Target molecules one after the other as a Set, since the cage dimensions are not modified. KWIK=7 is optimal for macromolecules and/or when docking ligands in Target. KWIK=7 include the KWIK 5 and 6 options, but when KWIK=7 the grid cage is modified, and only those grid-points located inside the ellipsoid included in the grid cage are considered.
1.7. New parameterisation for fluorine and heavier halogens
Through the years the hydrogen bonding energy functions of the GRID force field have been formulated for many acceptor atoms by fitting to experimental observations in crystal structures. Recently, a similar procedure was applied to fluorine, and an exhaustive inspection of the Protein Data Bank determined the hydrogen bonding pattern of aliphatic and aromatic carbon-bonded fluorines (Submitted at J.Med.Chem., 2004). 275 complexes from the PDB, whose protein structures have co-crystallised fluorine-containing ligands, were examined with regard to the binding mode and all crystal structures in which at least one hydrogen bond involves a fluorine atom from the ligand were selected. Thus, 49 complexes were retained providing 105 observed contacts classified as hydrogen bonds. By applying statistics, the hydrogen bonding geometry was described as a distribution function of the angle at the fluorine: a new specific angular function was consequently defined and inserted in the program GRID to estimate the effect of fluorine hydrogen bonds on the ligand-protein binding. All the fluorine-containing ligands collected from the PDB were docked within their corresponding protein binding sites: introducing the fluorine hydrogen bonding contribution improves the results of the docking experiments in terms of accuracy and ranking. For the heavier halogen atoms, miscellaneous tests on experimental and crystallographic data prompted us to the revision of their GRID Energy Variables. With 95% of confidence (within PDB and CSD data) heavier halogen do not form H-bonds and are classified as hydrophobic atoms.
1.8. The GREATER interface has been upgraded
The Graphic User Interface of the GREATER program has been improved introducing new tools giving access to wider GRID functionalities. Customisable methods have been inserted. New helps have been introduced. New GRIN keywords control has been activated. New functions have been inserted. Warning messages and colours and fonts can be fully customised using an option dialog box.
1.9. A pdf version of the manual is now available
The GRID User manual has been reformatted. The most important headings linked to each other when required. The new pdf format has been added, with the intent to allow easy navigation and printing. Please help us to make a better job, and let us know if something is not clear or wrong in the text. Contact us at http://www.moldiscovery.com
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