FIRSTThe most recent stable release of the FIRST is version 6.2. Both the stable release and the development version can be downloaded from Flexweb by following the download link in the left-hand menu. Also, the software can be run interactively through our web service. The web service is running FIRST 6.2. Note: if you have a problem with visualization of structure using Firefox browser, please use IE browser.
FIRST - Background InformationFIRST (Floppy Inclusions and Rigid Substructure Topography) is a program for identifying rigidity and flexibility in network graphs. The software is an implementation of a, "Computer implemented system for analyzing rigidity of substructures within a macromolecule", which was patented in 1998 by Don Jacobs and Michael Thorpe while at Michigan State University. The original release was programmed by Don Jacobs, with subsequent research and development by Brandon Hespenheide, Leslie Kuhn, AJ Rader and Michael Thorpe. This new release, FIRST6, represents a development stream that continues in the research group of Professor Thorpe, who is now in the Biophysics Theory Group at Arizona State University.
A variety of new input/output features have been added to the latest release. FIRST6 can analyze various 3-dimensional (3D) graphs, from a generic body-bar graph in which only the topology is defined (no distances) up to the full all-atom description of a protein structure defined in a Protein Data Bank (PDB) file. Dynamic memory allocation allows for very large structures to be analyzed; the current in-house record holder is the complete Cowpea Chlorotic Mottle Virus capsid structure. Having hydrogen atoms placed only on the polar atoms in the structure, this protein complex contains ~430,000 atoms. FIRST6 analysis of this macromolecule takes about 2 minutes.
The rigidity theory driving FIRST is based on a class of graphs known as body-bar graphs. Every site or vertex in the graph has degrees of freedom (DOF) associated with it. An isolated site has 3 DOF, representing the allowed motion in the x-, y-, and z-planes. A site with one connection or edge has 5 DOF (3 translations like the single site, plus 2 rotations). Finally, a site with 2 or more connections or edges will have a full 6 DOF corresponding to the 3 translations and 3 rotations available to a 3D "body". The connections or edges of the graph may be represented by up to 6 bars (5 bars for sites with only one atom). Each bar removes DOF from the system. Therefore, a constraint with 5 bars will have a more rigidifying effect on the system than 2 bars. A connection between a pair of sites implies that the distance between these two sites is constrained, and as such, they are often referred to as distance constraints.
Once a body-bar graph has been constructed, the pebble game algorithm is used to determine how the bars affect the degrees of freedom in the system. In this algorithm, each DOF is represented by a pebble. The game is to follow a small set of specific rules for moving the pebbles on and off the bars, one per bar. The game ends when no more valid moves exist. Upon completion of the pebble game it is possible to uniquely determine for each connection (remember, connections are composed of bars) whether it is possible to rotate about that connection (flexible) or whether the connection is locked (rigid). A collection of consecutive rigid bonds define a rigid region or rigid cluster. Likewise, a collection of flexible bonds may form a collective mode.
One key feature in FIRST6 is the ability to attenuate how each individual connection in a structure is modeled. The default behavior is that nonrotatable covalent bonds (ie. peptide bonds) remove 6 DOF, rotatabe covalent bonds remove 5 DOF, hydrogen bonds remove 4 DOF, and hydrophobic tethers remove 2 DOF. By using command-line options, it is possible to change the default number of bars used for hydrogen bonds and/or hydrophobic tethers. Furthermore, you may potentially modify every bond in the protein, either by using the "query network" menu system when running FIRST6, or by modifying the appropriate input files. Both methods are described in the manual. This feature is currently NOT available in FIRST online.
Perhaps the most important feature available in FLEXWEB is the FRODA module (Framework Rigidity Optimized Dynamics Algorithm) which moves the static results of a FIRST6 analysis into the realm of dynamics where we actually explore the conformational space available to flexible regions. The ability to explore conformational space leads to many new interesting conclusions about structural motion. For instance, regions which have been determined to be flexible by may not actually move very much because of local steric hindrance. Likewise, a small, independent rigid region may be flanked by two flexible regions allowing the whole rigid region to "move" as a block; a case we refer to as rigid, but mobile. In effort to improve the dynamics part of simulation Daniel Farrell recently developed new version of FRODA. The main advantages of which are:
- More realistic modeling of molecular flexibility;
- Faster performance;
- Better space sampling;
- Ability to simulate any type of biological molecules including RNA/DNA;
- Usage of backbone and side chain constrains which overall better preserves stereochemistry of the molecules;
- "Momentum" run option which allows fast exploration of large amplitude of motion.
The software is a work in progress; it works well provided the input file is formatted properly and does not contain erroneous data. There is a limited amount of error checking that occurs. FIRST6 will produce warnings when it notices small problems (and errors for big problems!) Bugs can be emailed to firstname.lastname@example.org. The main focus of this project is on the development of the FIRST6 software and flexweb, with a lesser emphasis on applications. As such, we would appreciate any feedback on the software, as it will help guide future directions for development. Finally, we will be available as much as possible for support, and hope you enjoy using the software!