FastContact

FastContact is a rapid estimate of contact and binding free energies for protein-protein complex structures. The programme was written in Fortran by Carlos J. Camacho and Chao Zhang at the Department of Computational Biology, University of Pittsburgh.

The abstract to the primary paper written on this programme describes it as follows:

Interaction free energies are crucial for analyzing binding propensities in proteins. Although the problem of computing binding free energies remains open, approximate estimates have become very useful for filtering potential binding complexes. We report on the implementation of a fast computational estimate of the binding free energy based on a statistically determined desolvation contact potential and Coulomb electrostatics with a distance-dependent dielectric constant, and validated in the Critical Assessment of PRotein Interactions experiment. The application also reports residue contact free energies that rapidly highlight the hotspots of the interaction.

FastContact is a server that estimates the direct electrostatic and desolvation interaction free energy between two proteins in units of kcal/mol. Users submit two proteins in PDB format, and the output is e-mailed back to the user in three files: One output file, and the two processed proteins. Besides the electrostatic and desolvation free energy, the server reports residue contact free energies that rapidly highlight the hotspots of the interaction and evaluates the van der Waals interaction using CHARMm. Response time is about one minute. The server has been successfully tested and validated, scoring refined complex structures and blind sets of docking decoys, as well as proven useful predicting protein interactions. FastContact offers unique capabilities from biophysical insights to scoring and identifying important contacts.

A web server was setup by Christoph Champ in July 2005 for running this programme.

The executable and full documentation is freely available at http://structure.pitt.edu/software/FastContact

Usage

Required user-input information

The user uploads two Protein Data Bank (PDB) format files, one 'receptor' and one 'ligand', along with their email address. The web server currently makes no distinction between chains; it simply reads in each line in the PDB file starting with an 'ATOM' field. The maximum number of residues is limited to 1500. The email address is where the output/results will be sent (as a file attachment). Hydrogen bonds and missing atoms are built and optimized on the uploaded structures using the molecular software CHARMm.

Optional parameters

Range of desolvation interaction: The default range is 6 Å, such that the potential smoothly goes to zero between 5 and 7 Å. This range is suggested for refined models, without overlaps and relatively snug interfaces. The user has the option of changing the range to 9 Å, approaching 0 between 8 and 10 Å. This modality is suggested for encounter complexes.

Minimization: The default setting for Hydrogen bond optimization and removal of minimal overlaps prescribes a short 3×20 ABNR minimization steps with fixed backbone using the program CHARMm and the PARAM19 Residue Topology File (RTF). However, the user is free to change this setting to a full atom minimization. This setting will work for single chains only and no gaps.

Patch end terminals with -NH3+ and -COOH: By default, the end terminal residues will be patched by CHARMm. In case the end terminals are missing from the structure, the user has the option of turning the patching feature off.

Output format and explanation

The results from a FastContact server run are returned to the user via email as a file attachment (with a normal response time of about one minute). The attached file is a gzipped archive (.tar.gz) containing three results files: (a) the main results file ('output.txt'); and, the processed (including H-bonds) (b) receptor PDB file and (c) the ligand PDB file. All of the files are prefixed with the user name (email prefix) and timestamp of the server run for easy reference.

The main results file ('output.txt') returns two components of a free energy function, electrostatic energy and desolvation free energy, and evaluates the solute the van der Waals energy using CHARMm. The latter is sometimes useful to compare between different models, but here it is given only as a reference since it is not used in the analysis of contacts. Often vdW energies larger than about -500 kcal/mol suggest structural overlaps. Although FastContact smooths the potentials to tolerate some limited overlaps, these are, in general, detrimental to the quality of the computational estimates.

Keywords

PDB, docking, free energy scoring, contact potential, binding free energy, protein interactions, complex structure, binding mechanism, recognition, desolvation

See also

• Dr. Carlos J. Camacho Laboratory
• SmoothDock

References

Further reading

• Camacho CJ, Ma H, and Champ PC (2006). Scoring a diverse set of high-quality docked conformations: A metascore based on electrostatic and desolvation interactions. Proteins, 63(4):868-77.

External links

• FastContact Server
• FastContact binaries — available for download