FastContact

From Christoph's Personal Wiki

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.[1]

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

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

Contents

Abstract

The abstract to the primary paper written on this program 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.[1]

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.[2]

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

Examples

Below is the output from a run of 1NPE ("receptor") and 1KLO ("ligand"), using the default optional parameters:

 ----- SUMMARY ENERGIES -----------------------
  Electrostatic (4r) Energy:   1.1973446 kcal/mol
  Desolvation  Free  Energy:   18.1253168 kcal/mol
  van der Waals (CHARMm19) :   13901.7 kcal/mol
 ----------------------------------------------
  If vdW > -500 kcal/mol, structures might overlap
  Affinity = Elec + Desol + Config. entropy*
  *For a given pair of proteins,
   Config. entropy ~ 5-to-15 kcal/mol
 ----------------------------------------------
 Top 20 Min & Max ligand residues contributing to the binding free energy
  -3.819   16 LYS
  -3.209   15 THR
  -1.925   78 LEU
  -1.714   65 ASN
  -1.124   67 VAL
  -0.815   33 GLU
  -0.733   30 LYS
  -0.708   64 PRO
  -0.547   68 GLY
  -0.465   11 ILE
  -0.397   76 GLU
  -0.329   81 ILE
  -0.254   84 THR
  -0.223   31 ARG
  -0.204   94 GLU
  -0.156   80 CYS
  -0.155   42 ASP
  -0.085   55 PRO
  -0.076   62 ILE
  -0.074   77 CYS
 -----------------
   0.084   18 VAL
   0.088   39 TYR
   0.088   34 LEU
   0.093   85 ALA
   0.098   71 ASN
   0.108   10 ALA
   0.117   69 ASN
   0.129   72 ARG
   0.152   60 ASP
   0.220   38 GLY
   0.523   36 ASP
   0.852   66 ALA
   1.693   12 VAL
   1.737   13 PRO
   2.116   93 LYS
   3.283   17 GLU
   4.072   63 ASP
   6.495   37 ASP
   6.739   14 LYS
   7.520   79 LYS
 Top 20 Min & Max ligand residues contributing to the desolvation free energy
  -2.081   67 VAL
  -1.502   15 THR
  -1.171   64 PRO
  -1.032   12 VAL
  -0.556   66 ALA
  -0.428   13 PRO
  -0.244   81 ILE
  -0.071   19 VAL
  -0.021   78 LEU
  -0.005   82 TYR
  -0.002   94 GLU
   0.000   18 VAL
   0.000   25 THR
   0.000   24 PRO
   0.000   23 CYS
   0.000   22 HIS
   0.000   21 THR
   0.000   20 CYS
   0.000    9 CYS
   0.000    8 SER
 -----------------
   0.007   33 GLU
   0.016   83 ASN
   0.020   84 THR
   0.040   77 CYS
   0.043   62 ILE
   0.053   34 LEU
   0.165   68 GLY
   0.223   38 GLY
   0.241   93 LYS
   0.276   16 LYS
   0.360   80 CYS
   0.552   11 ILE
   1.330   69 ASN
   1.433   17 GLU
   1.447   37 ASP
   2.429   65 ASN
   2.896   30 LYS
   3.185   63 ASP
   4.214   79 LYS
   6.304   14 LYS
 Top 20 Min & Max ligand residues contributing to the electrostatics energy
  -4.143   65 ASN
  -4.095   16 LYS
  -3.629   30 LYS
  -1.905   78 LEU
  -1.706   15 THR
  -1.212   69 ASN
  -1.017   11 ILE
  -0.822   33 GLU
  -0.712   68 GLY
  -0.516   80 CYS
  -0.397   76 GLU
  -0.274   84 THR
  -0.223   31 ARG
  -0.202   94 GLU
  -0.155   42 ASP
  -0.120   62 ILE
  -0.114   77 CYS
  -0.085   81 ILE
  -0.085   55 PRO
  -0.072   35 CYS
 -----------------
   0.078   70 CYS
   0.085   18 VAL
   0.088   39 TYR
   0.090   85 ALA
   0.098   71 ASN
   0.108   10 ALA
   0.129   72 ARG
   0.152   60 ASP
   0.436   14 LYS
   0.463   64 PRO
   0.523   36 ASP
   0.887   63 ASP
   0.957   67 VAL
   1.408   66 ALA
   1.850   17 GLU
   1.875   93 LYS
   2.165   13 PRO
   2.724   12 VAL
   3.306   79 LYS
   5.048   37 ASP
 Top 20 Min & Max receptor residues contributing to the desolvation free energy
  -2.245  204 VAL
  -1.457  366 LEU
  -1.308  205 LEU
  -0.711  327 ILE
  -0.151  329 PRO
  -0.117  367 ALA
  -0.064  203 LYS
  -0.021  328 ASP
  -0.009  347 TYR
  -0.003  234 MET
   0.000   20 ASN
   0.000   19 ARG
   0.000   18 GLU
   0.000   17 LEU
   0.000   16 PRO
   0.000   15 LEU
   0.000   14 ARG
   0.000   13 GLU
   0.000   12 ILE
   0.000   11 LYS
 -----------------
   0.247  323 CYS
   0.250  365 PRO
   0.287  326 ASN
   0.333  191 ALA
   0.556  355 ASP
   0.557  364 ASN
   0.598  321 CYS
   0.781  184 VAL
   0.934  319 ARG
   1.053  189 HIS
   1.227  185 ASP
   1.299  373 LYS
   1.304  192 GLU
   1.306  183 TRP
   1.360  209 GLN
   1.364  206 GLU
   1.675  322 GLN
   1.927  324 ASN
   2.435  190 ARG
   3.132  325 ASP
 Top 20 Min & Max receptor residues contributing to the electrostatics energy
  -7.807  206 GLU
  -4.306  373 LYS
  -2.554  192 GLU
  -2.373  209 GLN
  -1.853  321 CYS
  -1.759  367 ALA
  -0.776  225 ASP
  -0.652  319 ARG
  -0.611  207 GLY
  -0.409  324 ASN
  -0.325  188 THR
  -0.251  349 THR
  -0.212  191 ALA
  -0.201  165 ASN
  -0.201  171 GLY
  -0.166  164 ASP
  -0.150  302 ASP
  -0.140  375 LYS
  -0.140  208 LEU
  -0.139  186 ALA
 -----------------
   0.258  125 ARG
   0.285  187 GLY
   0.287  167 GLY
   0.290  185 ASP
   0.294  353 TYR
   0.354  170 ASN
   0.354  372 ASP
   0.356  252 ARG
   0.407  227 LYS
   0.525  365 PRO
   0.563  316 ARG
   0.612  205 LEU
   0.826  202 ARG
   0.854  189 HIS
   0.942  355 ASP
   1.543  322 GLN
   3.056  184 VAL
   3.602  323 CYS
   3.722  190 ARG
   6.515  325 ASP
 Top 20 Min & Max receptor-ligand residue electrostatic contacts
  -4.666  206 GLU   16 LYS
  -2.732  209 GLN   30 LYS
  -2.641  206 GLU   15 THR
  -2.252  373 LYS   65 ASN
  -2.234  321 CYS   79 LYS
  -2.032  192 GLU   14 LYS
  -1.955  367 ALA   65 ASN
  -1.802  319 ARG   78 LEU
  -1.609  206 GLU   14 LYS
  -1.355  373 LYS   63 ASP
  -1.199  190 ARG   14 LYS
  -1.128  227 LYS   33 GLU
  -0.974  325 ASP   69 ASN
  -0.903  225 ASP   30 LYS
  -0.767  190 ARG   11 ILE
  -0.693  324 ASN   63 ASP
  -0.688  325 ASP   68 GLY
  -0.670  325 ASP   79 LYS
  -0.633  325 ASP   72 ARG
  -0.622  190 ARG   17 GLU
 --------------------------
   0.706  325 ASP   36 ASP
   0.707  324 ASN   67 VAL
   0.708  202 ARG   14 LYS
   0.783  206 GLU   17 GLU
   0.798  316 ARG   93 LYS
   0.891  319 ARG   79 LYS
   0.905  205 LEU   15 THR
   0.955  190 ARG   16 LYS
   1.021  206 GLU   13 PRO
   1.140  227 LYS   30 LYS
   1.300  325 ASP   63 ASP
   1.406  355 ASP   63 ASP
   1.519  325 ASP   66 ALA
   1.538  190 ARG   13 PRO
   1.760  322 GLN   79 LYS
   1.914  319 ARG   93 LYS
   2.939  190 ARG   12 VAL
   3.040  184 VAL   14 LYS
   3.583  323 CYS   79 LYS
   5.531  325 ASP   37 ASP
 Top 20 Min & Max receptor-ligand residue free energy contacts
  -4.213  206 GLU   16 LYS
  -2.605  206 GLU   15 THR
  -1.901  367 ALA   65 ASN
  -1.709  206 GLU   14 LYS
  -1.568  319 ARG   78 LEU
  -1.547  321 CYS   79 LYS
  -1.522  209 GLN   30 LYS
  -1.355  373 LYS   63 ASP
  -1.121  227 LYS   33 GLU
  -1.042  373 LYS   65 ASN
  -1.038  366 LEU   64 PRO
  -0.903  192 GLU   14 LYS
  -0.903  225 ASP   30 LYS
  -0.847  204 VAL   13 PRO
  -0.840  327 ILE   67 VAL
  -0.709  204 VAL   14 LYS
  -0.694  207 GLY   15 THR
  -0.633  325 ASP   72 ARG
  -0.619  190 ARG   17 GLU
  -0.580  366 LEU   65 ASN
 --------------------------
   0.856  364 ASN   65 ASN
   0.865  189 HIS   14 LYS
   0.962  190 ARG   16 LYS
   1.142  227 LYS   30 LYS
   1.203  189 HIS   30 LYS
   1.222  206 GLU   17 GLU
   1.228  319 ARG   79 LYS
   1.239  206 GLU   13 PRO
   1.357  183 TRP   14 LYS
   1.429  325 ASP   63 ASP
   1.599  325 ASP   66 ALA
   1.821  185 ASP   14 LYS
   1.963  355 ASP   63 ASP
   2.071  319 ARG   93 LYS
   2.147  190 ARG   13 PRO
   3.069  190 ARG   12 VAL
   3.114  322 GLN   79 LYS
   3.821  184 VAL   14 LYS
   4.197  323 CYS   79 LYS
   6.976  325 ASP   37 ASP
 ----------------------------------------------
                   THE END

See also

References

  1. 1.0 1.1 Camacho CJ and Zhang C (2005). FastContact: rapid estimate of contact and binding free energies. Bioinformatics, 21(10):2534-6.
  2. Champ PC and Camacho CJ (2007). FastContact: a free energy scoring tool for protein-protein complex structures. Nucleic Acids Res. (Web addition).

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

Personal tools