gameplan

The gameplan application analyzes a protein and a bound or docked ligand to determine points where solvent information may be interesting, runs szmap at these points, and then processes the results, formulating various hypotheses for ligand modification and identifying sites where water is stabilizing or destabilizing.

_images/4std_polar_attachment.png

Gameplan Hypothesis

Running Gameplan

The usual workflow starts with preparing the protein and ligand by adding hydrogens and assigning partial charges. See the Tutorial for a thorough discussion of preparation.

Next, run gameplan and view the results in VIDA using the WaterColor VIDA Extension to configure the annotations. On average, a gameplan calculation will take 4 to 8 minutes on Linux using four 2.8GHz processors, for example.

> gameplan -szmap_mpi_np 4 -prefix 2xdl_gameplan -p 2xdl_prot.oeb.gz -l 2xdl_lig.oeb.gz
> vida 2xdl_gameplan.oeb.gz

In Gameplan Hypothesis, the bonds in hot-pink represent an idea about how to modify the ligand to add a two-atom hydrogen-bond acceptor group that could interact favorably with nearby tyrosine residues. The yellow ball indicates that water makes a strong polar interaction at this site in the apo-protein.

When gameplan reads input molecules, it checks for missing hydrogens and missing partial charges and will halt if the input does not appear to be complete. The option -warn_if_missing_hydrogens can be used to prevent halting, but before using it you should analyze the problem to see if it is due to an error in the input or even a disagreement with OEChem as to the proper bond order and charge state for your molecule. Mistakes in encoding alternate conformation codes can, for example, lead to very long and very short bonds, with the short ones interpreted as double bonds. And aromatic or double bonds that are not flat enough can cause OEChem to think they are single bonds. You may need to use a text editor or VIDA’s builder tool to resolve any pathologies you find, and then rerun pch.

By default, gameplan hypotheses respect the hybridization of aromatic atoms in the input ligand. Specifying the option -sp3_aromatic will permit gameplan to explore the effect of a change of hybridization of aromatic atoms. Note that only the local hybridization at the attachment site is altered, often leading to odd-looking geometry. But the point is to generate fresh ideas for how you might modify your ligand.

Gameplan Results

Open the results in VIDA, highlight any part of the output in the List window, and run the WaterColor VIDA Extension to configure the annotation and focus the view to the region around the ligand. See the last section of chapter WaterColor VIDA Extension for a step-by-step guide to doing this.

_images/vida_gameplan_list_window.png

Gameplan List Window

gameplan results are organized into three main sections (see figure Gameplan List Window):

  1. An analysis of how well the ligand compares to the solvent in the binding site with colored annotation around atoms that indicates the type of site (figure Ligand Compared to apo Binding Site). The protein is also included here for context.
  2. A series of hypotheses for substituents that could be added to the ligand. Each attachment is modeled using dummy atoms that show up in hot-pink in VIDA, with annotation that indicates the type of site: polar, nonpolar and van der Waals (see figures Hypothesis for a Polar Substituent and Hypothesis for a Nonpolar/VDW Substituent).
  3. A (possibly empty) section showing stabilizing and destabilizing water sites (figure Stabilizing Site).
_images/vida23-gp-ligand.png

Ligand Compared to apo Binding Site

_images/vida24-gp-polar.png

Hypothesis for a Polar Substituent

_images/vida25-gp-nonpolar.png

Hypothesis for a Nonpolar/VDW Substituent

_images/vida26-gp-stbl.png

Stabilizing Site

Annotations are:

  • Yellow mesh sphere: polar site; the size of the sphere indicates the magnitude of the polar interaction.
  • Green mesh sphere: van der Waals site; the size of the sphere indicates the magnitude of the VDW interaction.
  • Green translucent sphere: non-polar site.
  • Purple top: mismatch site, where the ligand polarity does not match that of the solvent.
  • Small green and red spheres: stabilizing and destabilizing points, respectively.

Based on your results, you may want to modify your ligand to make it more compatible with the apo pocket solvent electrostatics, add a substituent based on the suggested hypotheses, displace a destabilizing water or carefully replace a stabilizing water, mimicking the interactions of the water.

Command Line Interface

A description of the basic command line interface can be obtained by executing gameplan with no arguments.

prompt> gameplan

will generate output similar to the following:

          :jGf:
        :jGDDDDf:          GGGG     A    M     M EEEEEEE PPPPP  L          A    N     N
      ,fDDDGjLDDDf,       G    G   A A   MM   MM E       P    P L         A A   NN    N
    ,fDDLt:   :iLDDL;     G       A   A  M M M M E       P    P L        A   A  N N   N
  ;fDLt:         :tfDG;   G  GGG  AAAAA  M  M  M EEEEE   PPPPP  L        AAAAA  N  N  N
,jft:   ,ijfffji,   :iff  G    G A     A M     M E       P      L       A     A N   N N
     .jGDDDDDDDDDGt.      G    G A     A M     M E       P      L       A     A N    NN
    ;GDDGt:''':tDDDG,      GGGG  A     A M     M EEEEEEE P      LLLLLLL A     A N     N
   .DDDG:       :GDDG.
   ;DDDj         tDDDi    Copyright (c) 2009-2015
   ,DDDf         fDDD,    OpenEye Scientific Software, Inc.
    LDDDt.     .fDDDj     Version: 1.2.1
    .tDDDDfjtjfDDDGt      Release: 20150305
      :ifGDDDDDGfi.       OEChem version: 1.9.2 20150305
          .:::.           Platform: redhat-RHEL5-g++4.1-x64
  ......................
  DDDDDDDDDDDDDDDDDDDDDD
  DDDDDDDDDDDDDDDDDDDDDD

  Licensed for the exclusive use of Company Name.
  Licensed for use only in Site.
  License expires on August 15, 2015.

To cite please use the following:
GAMEPLAN, version 1.2.1, OpenEye Scientific Software, Inc.,
Santa Fe, NM, USA, www.eyesopen.com, 2015.

No arguments specified on the command line
gameplan : <protein> <ligand> [<output>]
Required parameters:
    -protein : Input protein molecule file
    -ligand : Input ligand molecule file.
For more help type:
  gameplan --help

Required Parameters

-protein <filename>
-p <filename>

[keyless parameter 1]

The format must be one that retains partial charges: OEBinary, Tripos .mol2, or DelPhi flavor PDB (where there is radii in the occupancy field and charge in the B-factor field).

The file format of the input file is automatically determined from the file extension. The extensions .oeb, .oeb.gz can be OEBinary; .mol2 for Tripos Mol2 files; .pdb for PDB format files.

File type Extension
OEBinary .oeb .oeb.gz
PDB(DelPhi) .pdb .ent .pdb.gz .ent.gz
MOL2 .mol2 .mol2.gz

Warning

Charges and radii are expected to be in this file and the results will be meaningless if they are missing.

-ligand <filename>
-l <filename>

[keyless parameter 2]

The format must be one that retains partial charges: OEBinary, Tripos .mol2, or DelPhi flavor PDB (where there is radii in the occupancy field and charge in the B-factor field).

The file format of the input file is automatically determined from the file extension. The extensions .oeb, .oeb.gz can be OEBinary; .mol2 for Tripos Mol2 files; .pdb for PDB format files.

File type Extension
OEBinary .oeb .oeb.gz
PDB(DelPhi) .pdb .ent .pdb.gz .ent.gz
MOL2 .mol2 .mol2.gz

Warning

Charges and radii are expected to be in this file and the results will be meaningless if they are missing.

Command Line Options

Output Options

-prefix <prefix>

Prefix used to name output files. Using -prefix FOO will create results in an OEBinary file named FOO.oeb.gz (see -output). Additionally, a parameter file named FOO.param (see -param) and a log file named FOO.log (see -log).

[default = gameplan]

-output <filename>
-o <filename>

[keyless parameter 3]

OEBinary output file (.oeb or .oeb.gz), containing calculated results.

If not specified, -prefix will be used to name the output.

Parameters

-merge <number>

[default = 0.35 Å]

Distance cutoff for merging two sample points.

-sp3_aromatic <bool>
-sp3aromatic <bool>

Sample sp3 hybridization at each aromatic ligand atom.

[default = false]

-stabilization <bool>
-stbl <bool>

Search for regions where water is stabilized or destabilized by in the protein/ligand complex.

[default = true]

-clean <bool>

Remove temporary files written by szmap during this run of gameplan.

[default = true]

-light_background
-light_bkg
If specified, annotation colors will be adjusted to better match a white background. By default, they are chosen to match a dark background.
-warn_if_missing_hydrogens
If specified, missing hydrogens will not terminate the program, but will instead generate a warning message. Otherwise, missing hydrogens on the ligand or on more than 10 percent of the protein heavy atoms will cause gameplan to fail.

MPI Options

-szmap_mpi_np <number>
Run gameplan calculations in MPI miltiprocessor mode using the specified number of processors. If an MPI hostfile is not specified with the -mpi_hostfile option all processor will be launched on the local machine.
-szmap_mpi_hostfile <filename>

Run gameplan calculations in MPI miltihost mode using the specified MPI hostfile. If an MPI hostfile is not specified all processes will be run on the local machine. The hostfile format is a text file with each line specifying a machine and the number of processes to launch on it.

The following example hostfile specified 3 hosts that can run up to 4, 2 and 5 processes respecitively.

host1.mydomain.com slots=4
host2.mydomain.com slots=2
host3.mydomain.com slots=5

This example hostfile would typically be used with -szmap_mpi_np 11 to make use of all the processors (4+2+5=11).

Note that multiprocessor is only supported on the local machine under Windows, and in homogeneous enviroments for other architectures (i.e., machines with the same operating system enviroment).

Other Options

-param <filename>
Defines the control parameter file. This file can contain a collection of parameters which can be used instead of writing each parameter to the command-line. In addition, the parameter file written by any gameplan run (see -prefix) can be used with the -param flag in subsequent gameplan runs. Any command given explicitly on the command line will supersede any command found in a file specified with the -param flag.
-logfile <filename>
-log <filename>
If specified, this will override the filename created from -prefix. Specify -log - to send to standard-output.
-progress <style>

How to display szmap progress information:

Style Output
none no progress shown
dots print a period (.) for every point tested
percent print percentage complete every 10 points
log print percentage to log file

[default = dots]

-verbose
-v
Print additional information to log during calculations.

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