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<h2 align="center">How to use LigBuilder: LINK </h2>
<hr>
<p> The major function of LINK is constructing
ligand molecules for the target protein by applying the linking
strategy. Just like GROW, all the molecules are also
originated from a "seed" structure. But here, the seed
structure contains several pieces of chemical fragments. The
program will try to link them into integrated molecules.</p>
<p> Synopsis of running LINK:</p>
<p> <font
color="#FF0000"><strong>link parameter_file</strong></font></p>
<p> For example:</p>
<p> link
link.index </p>
<p> The parameter file assembles all the
information necessary to run LINK as you wish. You should edit
the parameter file before running LINK. The key words appeared in
this parameter file are explained in the following.</p>
<p> First, tell the program about the input
files:</p>
<p> <font color="#0000FF">SEED_LIGAND_FILE</font>:
The Mol2 file presenting the "<font color="#FF0000">seed</font>"
structure. As mentioned above, this is absolutely necessary
because the "seed" is the mother of all the resultant
molecules. Therefore, it will be ideal if the seed structure
holds the key features of the prospective ligands. LigBuilder
itself does not provide a program to generate the seed structure
so you need to prepare it yourself. For more instruction of how
to prepare a seed structure, please refer to the <a
href="skill.html#subject_1">Advanced Skills</a> section.</p>
<p> <font color="#0000FF">POCKET_ATOM_FILE</font>:
The corresponding file given by POCKET.</p>
<p> <font color="#0000FF">POCKET_GRID_FILE</font>:
The corresponding file given by POCKET.</p>
<p> <font color="#0000FF">PARAMETER_DIRECTORY</font>:
The path of the directory "<font color="#0000FF">parameter</font>".
Under this directory, there are force field parameters used by
LigBuilder. Parameters for atoms, bonds, and torsions are cited
from Tripos force field. This directory is used by POCKET, GROW,
LINK and PROCESS.</p>
<p> Then, there are the definitions of three
fragment libraries:</p>
<p> <font color="#0000FF">BUILDING_BLOCK_LIBRARY</font>:
The path of the building-block fragment library. The default one
is "<font color="#0000FF">fragment.mdb</font>".</p>
<p> <font color="#0000FF">FORBIDDEN_STRUCTURE_LIBRARY</font>:
The path of the forbidden substructure library. The default one
is "<font color="#0000FF">forbidden.mdb</font>".</p>
<p> <font color="#0000FF">TOXIC_STRUCTURE_LIBRARY</font>:
The path of the toxic substructure library. The default one is
"<font color="#0000FF">toxicity.mdb</font>".</p>
<p> If you are a novice to LigBuilder, you can
simply adopt the default settings for the above three fragment
libraries. If you want to learn how to edit them to meet your own
purpose, please refer to the <a href="skill.html">Advanced Skills</a>
section.</p>
<p> LINK builds up molecules with three kinds
of manipulations, i.e. growing, linking, and mutation. The
following three parameters will control how much these
manipulations will be applied, respectively:</p>
<p> <font color="#0000FF">GROWING_PROBABILITY</font>:
For the current version of LINK, growing manipulation is the
essential manipulation. So please fix this parameter to 1.00.</p>
<p> <font color="#0000FF">LINKING_PROBABILITY</font>:
For LINK, linking manipulation is also essential. So please fix
this parameter to 1.00 too.</p>
<p> <font color="#0000FF">MUTATION_PROBABILITY</font>:
LINK also employs a "smart mutation" manipulation to
improve the binding affinity of ligand molecules. We recommend
this parameter to be 0.50.</p>
<p> Then there are a set of chemical viability
rules, including "<font color="#0000FF">APPLY_CHEMICAL_RULES</font>",
"<font color="#0000FF">APPLY_FORBIDDEN_STRUCTURE_CHECK</font>",
"<font color="#0000FF">APPLY_TOXIC_STRUCTURE_CHECK</font>",
"<font color="#0000FF">MAXIMAL_MOLECULAR_WEIGHT</font>",
"<font color="#0000FF">MINIMAL_MOLECULAR_WEIGHT</font>",
"<font color="#0000FF">MAXIMAL_LOGP</font>", "<font
color="#0000FF">MINIMAL_LOGP</font>", "<font
color="#0000FF">MAXIMAL_HB_DONOR_ATOM</font>", "<font
color="#0000FF">MINIMAL_HB_DONOR_ATOM</font>", "<font
color="#0000FF">MAXIMAL_HB_ACCEPTOR_ATOM</font>", "<font
color="#0000FF">MINIMAL_HB_ACCEPTOR_ATOM</font>", "<font
color="#0000FF">MAXIMAL_PKD</font>", and "<font
color="#0000FF">MINIMAL_PKD</font>". To learn what these
parameters mean and how to set them, please refer to the <a
href="skill.html#subject_2">Advanced Skills </a>Section.</p>
<p> LINK also uses Genetic Algorithm (GA) to
develop and evolve molecules. Unlike GROW, LINK is run under <font
color="#0000FF">steady-state</font><font color="#FF0000"> </font><font
color="#000000">mode</font><font color="#FF0000">. </font>The
rough procedure is like this: (1) Generate the initial population
based on the seed structure; (2) Choosing a "mother"
molecule from the current population; (3) Generate new
molecule(s) by performing structural manipulations on the mother
molecule; (4) Check the new molecule(s): if they are better than
the worst molecule(s) in the current population, then replace
them. (5) Go to Step 2 until the pre-set number of generations
has been reached.</p>
<p> There are two parameters for setting up
this GA procedure:</p>
<p> <font color="#0000FF">NUMBER_OF_GENERATION:
</font><font color="#000000">Number of generations (GA circle) to
go through. Typically 20,000 ~ 30,000 generations will be enough.</font></p>
<p> <font color="#0000FF">NUMBER_OF_POPULATION:
</font><font color="#000000">Size of the population. We recommend
the population to be around 1,000.</font></p>
<p> The last two items in the parameter file
are concerning with the outputs:</p>
<p> <font color="#0000FF">POPULATION_RECORD_FILE</font>:
This file will record the final population in LigBuilder LIG
format. It provides the possibility of resuming a former job.
This is explained in the <a href="skill.html#subject_6">Advanced
Skills</a> section.</p>
<p> <font color="#0000FF">LIGAND_COLLECTION_FILE
</font>: This is the output file of LINK. During the GA
procedure, all the molecules which have connected the seed
structure successfully will be record in this file. Please notice
that these molecules also meet the chemical rules you set above.
This file is in LigBuilder LIG format so it can be analyzed by
PROCESS.</p>
<p> Running LINK takes more time than running
GROW. If run on a SGI O2/R10000/150M workstation, a typical LINK
job will take 6~7 hours. The overall running time is roughly
proportional to the number of GA generations and the size of the
population.</p>
<hr>
<p align="center"><a href="index.html">[Content]</a> <a
href="intro.html">[Introduction]</a> <a href="download.html">[Download]</a>
<a href="install.html">[Install]</a> <a href="overview.html">[Overview]</a>
<a href="pocket.html">[POCKET]</a> <a href="grow.html">[GROW]</a>
[LINK] <a href="process.html">[PROCESS]</a> <a href="skill.html">[Skills]</a>
<a href="faq.html">[FAQs]</a></p>
<p align="center"><font size="2"><em>(These web pages are edited
by Dr. Renxiao Wang. Latest update: August, 2000)</em></font></p>
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