Putative Active Sites with Spheres

 

Keywords: protein active site, binding site, cavity detection, buried volume, molecular modeling, computer-aided drug design

Summary

PASS (Putative Active Sites with Spheres) is a simple computational tool that uses geometry to characterize regions of buried volume in proteins and to identify positions likely to represent binding sites based upon the size, shape, and burial extent of these volumes. PASS'S utility as a predictive tool for binding site identification is tested by predicting known binding sites of proteins in the PDB using both complexed macromolecules and their corresponding apo-protein structures. The results indicate that PASS can serve as a front-end to fast docking. The main utility of PASS lies in the fact that it can analyze a moderate-size protein (~ 30 kD) in under twenty seconds, which makes it suitable for interactive molecular modeling, protein database analysis, and aggressive virtual screening efforts. As a modeling tool, PASS (i) rapidly identifies favorable regions of the protein surface, (ii) simplifies visualization of residues modulating binding in these regions, and (iii) provides a means of directly visualizing buried volume, which is often inferred indirectly from curvature in a surface representation. PASS produces output in the form of standard PDB files, which are suitable for any modeling package, and provides script files to simplify visualization in Cerius2^®, InsightII^®, MOE^®, Quanta^®, RasMol^®, and Sybyl^®. PASS is freely available to all.

Full Text Article

"Fast Prediction and Visualization of Protein Binding Pockets With PASS"

G. Patrick Brady, Jr. and Pieter F.W. Stouten

Journal of Computer-Aided Molecular Design, 14: 383-401, 2000

 PDF (Adobe Acrobat)         HTML

Downloads

PASS is free to all in executable form (no guarantees are made or implied, however, by the author or by DuPont Pharmaceuticals regarding its implementation or performance).
 

SGI Irix 6.5

pass10_sgi.tar.gz  (gzipped)
pass10_sgi.tar.Z  (compressed)
pass10_sgi_n32mips3.tar.gz  (gzipped)
pass10_sgi_n32mips3.tar.Z  (compressed)

SunOS 5.6

pass10_sun.tar.gz  (gzipped)
pass10_sun.tar.Z   (compressed)

Linux (2.0.36 and )

pass10_2.0.36linux.tar.gz  (gzipped)
pass10_2.0.36linux.tar.Z   (compressed)
 

Running PASS

PASS is  trivial to run from the unix command line.  To run PASS on a protein in PDB file "myprotein.pdb," simply type "pass myprotein.pdb."  By default, PASS removes water molecules from the PDB file and removes all protein hydrogen atoms if less than 20% of the input protein atoms are hydrogen.  PASS offers a host of other options that are available via command-line flags.  A full description of PASS' usage and command-line flags can be obtained by running "pass" with no command-line arguments.
 
 

Troubleshooting

  The most prevalent cause of PASS crashes is nonstandard PDB entries. For instance, in regions of ambivelent electron density, multiple copies of certain groups or residues often appear in the PDB file (with a letter preceding each residue name to distinguish them). E.g. the following snippet from PDB entry 1hyt (thermolysin):

--------------------------------------------------------------------------------
...
ATOM     58  N   GLY    10      21.439  51.310  15.580  1.00 13.52      1HYT 217
ATOM     59  CA  GLY    10      21.833  49.927  15.667  1.00 14.69      1HYT 218
ATOM     60  C   GLY    10      23.318  49.768  15.939  1.00 22.26      1HYT 219
ATOM     61  O   GLY    10      24.055  50.724  16.134  1.00 20.70      1HYT 220
ATOM     62  N   ARG    11      23.750  48.533  15.811  1.00 11.91      1HYT 221
ATOM     63  CA  ARG    11      25.120  48.151  16.033  1.00 12.60      1HYT 222
ATOM     64  C   ARG    11      25.627  47.473  14.816  1.00 16.25      1HYT 223
ATOM     65  O   ARG    11      24.959  46.582  14.318  1.00 15.58      1HYT 224
ATOM     66  CB  ARG    11      25.156  47.133  17.156  1.00 17.45      1HYT 225
ATOM     67  CG  ARG    11      26.230  47.384  18.179  1.00 31.50      1HYT 226
ATOM     68  CD BARG    11      26.273  46.349  19.286  0.50100.00      1HYT 227
ATOM     69  CD AARG    11      26.191  46.343  19.322  0.50  5.13      1HYT 228
ATOM     70  NE BARG    11      25.496  46.791  20.423  0.50 30.12      1HYT 229
ATOM     71  NE AARG    11      25.291  46.713  20.425  0.50 38.48      1HYT 230
ATOM     72  CZ BARG    11      25.769  47.887  21.131  0.50 36.09      1HYT 231
ATOM     73  CZ AARG    11      24.439  45.887  21.057  0.50 21.98      1HYT 232
ATOM     74  NH1BARG    11      26.855  48.650  20.886  0.50 42.74      1HYT 233
ATOM     75  NH1AARG    11      24.327  44.602  20.731  0.50 24.67      1HYT 234
ATOM     76  NH2BARG    11      24.925  48.213  22.113  0.50 16.46      1HYT 235
ATOM     77  NH2AARG    11      23.661  46.370  22.045  0.50 14.65      1HYT 236
ATOM     78  N   GLY    12      26.831  47.801  14.410  1.00 11.29      1HYT 237
ATOM     79  CA  GLY    12      27.396  47.171  13.215  1.00 11.71      1HYT 238
ATOM     80  C   GLY    12      28.206  45.906  13.524  1.00 11.99      1HYT 239
ATOM     81  O   GLY    12      28.298  45.433  14.682  1.00 14.99      1HYT 240
...
--------------------------------------------------------------------------------

To remedy such problems, edit the PDB file so as to force it to be standard. In this case, delete either the "A" or "B" copy of ARG 11 and blank-out the letter preceding the residue name.

Please email me bugs and/or troubleshooting tips so that I can rectify the code or include an appropriate suggestion on this page. Thanks.

  Financial support for this project was provided by DuPont Pharmaceuticals Co.

  G.Patrick.Brady@dupontpharma.com