Overview (README)

Introduction.

This chapter is mainly added to guide the user through the hypertext representation of the writeup. This chapter can get activated via the APROPO command, or by using the WWW entry for WHAT IF on swift.

WHAT IF was written with proteins in mind. Many options are available to visualize proteins (see the menus GRAFIC for normal molecular display, GRATWO for two dimensional graphics, GRAEXT for special effects, RIBBON in PORNO for very beautiful graphics or molecular pornography, COLOUR to colour atoms, residues, molecules, etc., PSTPLT for postscript plots).

You can perform many calculations on proteins. See HBONDS for hydrogen bonds, ACCESS for accessibility calculations, CHIANG for torsion angle manipulations, BUILD to do ab-initio building, REFINE to patch up your structure after you mugged it up manually, GROMOS to interface to the GROMOS energy minimization and molecular dynamicsprogram, GRID to interface to the GRIN and GRID potential energy calculation programs, HSSP to manipulate HSSP files (multiple sequence alignments), WALIGN for sequence operations. Model building by homology is done via the BLDPIR command in the PIRPSQ menu. The command CHECK activates a menu for protein structure verification, all thinkable and unthinkable errors will be detected, and you can get (completely automatically) a report written as if it is an article to be submitted.

The WATER menu has several options to manipulate water molecules. In the ANACON menu you will find contact analysis and bump checking options. GROMOS molecular dynamics movies can be displayed from the ANATRA menu. All superposition options, inclusive the fully automatic protein superposition module can be activated from the SUPPOS menu, however, if you want to run the automatic superposition option against the whole database, you should use the 3SSP menu. The CONOLY menu can be used to work with Connolly's surface area calculation and visualization program.

The NMR menu holds NMR specific options like multiple structure display, multiple structure superposition, multiple structure entry etc. The XRAY menu holds several XRAY specific commands, for example, MASMAP to massage electron density maps, CHKMDF to visually inspect h, k, l, F, sigma files, MAPEDT to edit envelope maps and SYMTRY for symmetry operations.

The TABLES menu holds a molecular spread sheet. All WHAT IF options that produce residue related output (e.g. accessibilities, secondary structure, packing quality, etc.) can write tables in this spread sheet. This spread sheet removes the hasle of manually comparing many sheets of paper with the output of many different programs.

The DGLOOP menu holds options to use the fragment database, for example to make loop insertions. The SEARCH menu helps you searching for complicated situations in your protein like atoms potentially involved in a hydrogen bond which actually are not, but are fully buried, or similarly complicated combined questions. The SCAN3D menu holds all options to manipulate the very special relational database. This database is best compared with the very nice (but expensive) IDITIS (tm) database system. SCAN3D is less extensive, but fully integrated.

Interaction with what if

WHAT IF has two kinds of options, GENERAL options and menu specific options that are spread over the MENUS. GENERAL options are described in the chapter on GENERAL options.

WHAT IF is based on a so-called SOUP. This SOUP holds all information like coordinates, database hits, parameters, atomic colours, energy values etc. The SOUP menu can be used to manipulate the SOUP.

Most graphical options are performed from the GRAFIC menu, but also options outside the GRAFIC menu can produce graphical output. For example, the SHOHBO option in the HBONDS menu will calculate hydrogen bonds and list them in the text window. However, if the graphics window has been activated (by using the command GRAFIC earlier) the hydrogen bonds are also displayed in the graphics window.

Examples

Many examples are available to give you an impression of the capabilities of WHAT IF. A couple hundred SCRIPT files are available that display the program's possibilities. There is also a set of SCRIPT files available to aid you with undergraduate student teaching.

Calculations

There are many things WHAT IF can calculate for you. The ACCESS menu does all kinds of accessibility calculations. Simple surface area calculations, as well as buried surface differences upon drug binding (DIFACC). Surface can be compared with respect to database averages (ANASRF).

You can calculate atomic distances (DIST), clashes (BUMPS), or environments (NAYB). The results can be graphically represented (GRAFIC). Contacts with waters (WATER), buried waters, or the distance of atoms to bulk water (CABWAT) can be calculated.

You can calculate hydrogenbonds (HBONDS), and you can even optimise hydrogenbond networks (HB2NET). These can be displayed (HB2GRA), and errors in ambihuous hydrogenbonding residues can be detected ((HB2LFR).

There are many different contact analysis options (ANACON). For example, atomic contacts (CONATM) or residue based contact analysis (CONRES) can be performed and graphically represented. These graphical contact plots, like all two dimensional graphics in WHAT IF, are pickable. Saltbridges (SHOSBR) are a special case of contact analysis. The SETVDW menu allows you to use any desired Van der Waals` radius during these calculations.

The SUPPOS menu has many different superposition options. The most intelligent option probably is the fully automatic superpositioning of protein structures. In contrast to many other methods, this module does not require human intervention. Several options exist to compare covalently identical, or covalently highly similar molecules (COMPAR, EQUAL).

The NMR menu allows you to do a few operations on many covalently identical molecules at a time.

The molecular spreadsheet TABLES provide a useful tool for organising data at the residue level.

The CHIANG menu allows you to display (SHOCHI), or manipulate (SETCHI, RNGCHI) torsion angles. The TORS command allows you to do this interactively. The automatic ligand topology maker (DRGTOP) makes it possible to also interactively manipulate small molecule torsion angles.

WHAT IF provide several small molecule related options in the DRUG menu. It can read small molecules in PDB format (GETMOL), MOL2 format (GETML2), or in CSD format (GETCSD). Intefaces exist to the LIGIN and FLEXX drug docking programs, but some limited docking facilities are an integral part of WHAT IF (DENFIT, DENOPT).

The Schneider and Sander HSSP files that hold multiple sequence alignments for all known structures can be read (SHOHSP), use for variability analysis (GETHSP), or for building models (BLDHSP).

Th toy NEURAL network can be used to experiment a bit with small neural network related problems.

WHAT IF can operate ten electron density maps at a time. Maps should have the MFF format, or formatted Xplor format. Most map formats can be converted to either of these two formats by the CCP4 map converter.

The CAVITY options allows you to visualise cavities.

The CHKMDF menu allows the crystallographers to visualise reciprocal space. HKL,F,sigma files can be displayed, as well as differences between datasets.

WHAT IF provides the most extensive and most intelligent symmetry menu of all molecular modelling related packages. Most options, eg. hydrogen bond analysis, accessibility calculations, contact analysis, etc, can automatically incorporate symmetry related partners if requested.

The REFI option regularises structures that are about OK. The CRUDE option, as the name already suggests, does an extremely crude fixing of structures that have really large errors in them.

The SEARCH menu allows you to answer complicated questions like: "Where are the buried unsatisfied hydrogen bond donors/acceptors that are not involved in a hydrogen bond?". This menu allows for the flexible combination of most of WHAT IF's calculation options.

The WALIGN menu is a story in itself. It allows for several rather intelligent sequence analysis possibilities. Iterative profile alignment (PROF2D) is the basis of this menu. Correlation analysis (CORREL) helps you determine essential (functional or structural) amino acids in your sequence(s).

Graphics

WHAT IF has several graphics menus. The command GRAFIC activates the default graphics menu. Here you can do all normal operations like drawing ZONES of residues or SPHERE s. GRABB will draw back bone, GRACA will draw C-alpha traces, etc. Salt bridges, hydrophobic clusters, potetial water positions (POTH2O), are all displayable. The OPTVIE option optimises the view for you.

The GRATWO menu does two dimensional graphics. PHIPSI plots, B-factor plots (BFPLOT), etc., can be drawn and interactively inspected.

The ITMADM menu allows you to book-keep the graphical objects GETITM will get yesterdays objects (called items) back, for example.

The GRAEXT command holds some rather special graphics commands. For example with ARROW you can draw an arrow that you can than place anywhere at the screen you want. LINATM allows you to draw lines between atoms. PLUTO draws 3D plots much like the old pluto program did in 2D. CELL draws a fram around your crystallographic cell. There are also some options to draw hidden line removed, depth cueued SPLINE plots.

The PORNO menu holds the very fancy graphics options, the so-called molecular pornography. Here you find the interface to the RIBBON program and to the PLUTON program.

You can also LABEL atoms any way you want in the label menu.

The COLOUR menu holds options like COLCHG to colour by charge, COLROW to colour by search hit, COLBFT to colour by B-factor, but also options like COLBB to colour the backbone, etc.

Databases

The WHAT IF databases are famous. It is the only database system that does not require that you first install a very expensive database driver. As the databse code is an integral paret of WHAT IF, you get no additional installation overhead. You can search in the PDB for secondary structure, mutability, accessibility, hydrogenbonds, torsion angles, 3D contacts, etc., and that all at a speed that you wont believe, not even when you see it happen. The WHAT IF 3D database is so fast and flexible that the most complicated queries can still be performed on a small PC. The command SCAN3D activates this menu.

WHAT IF also is the scientific father of the PDBFINDER databse. This PDBFINDER can be queried by many different programs, e.g. SRS. The SELECT options allow you to search for example for proteases solved at better than 2.5 A resolution that are shorter than 250 amino acids, etc.

Protein structure verification

You can CHECK the quality of protein structures or models for many different kinds of errors. The WHAT IF option FULCHK produces the most elaborate checking output one can think of. The checks performed range from trivial bond length, torsion angle, and surface checks to highly advanced contact analysis and hydrogen bond network checks.

Using GROMOS

The program GROMOS is one of the best molecular dynamics and energy minimisation programs. However, the authors had science in mind when they designed it, and not you, the user. It is therefore an understatement to say that GROMOS is a bit hard to use. The WHAT IF menu WREGRO changes that. It has the useful option WREGRO to get started, and get all the GROMOS files created. But it also has the extremely intelligent FASTEM and FASTMD options. These options, as the names already suggest, do EM and MD for you. But they are so smart that if you make a mistake, they read the GROMOS output, decide on the correction, and automatically run the, now corrected, jobs again.

Modelbuilding by homology

WHAT IF is famous for its homology modelling module. The world wide modelling competition in 1994 was a great success for the WHAT IF modelling options, beating all commercial programs.

Acknowledgements

Read the chapter called acknowledgements to see who actually did the work that created this wonderful program!