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.[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
- ↑ 1.0 1.1 Camacho CJ and Zhang C (2005). FastContact: rapid estimate of contact and binding free energies. Bioinformatics, 21(10):2534-6.
- ↑ 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
- FastContact Server
- FastContact binaries — available for download
