作者 / 七八分
公众号 / 叮当学术
本期内容记录以下在Schrödinger中批量对蛋白-配体复合物基于配体的位置生成对接盒子的方法。可用于反向对接，特别是对于含原配体的靶蛋白，通常会以原配体位置定义活性位点，以对小分子进行靶标预测。
这里笔者使用三个（实际上可以很多个）已经处理好的蛋白-配体复合物结构.maegz文件，也可以是其它.pdb、.mae等Schrödinger支持的文件格式；
运行Schrodinger Power Shell，输入命令进入结构文件所在的路径，如：
cd E:\Directory\TargetFishing\Test
下面可以使用generate_glide_grids_startup.py脚本来对蛋白生成对接盒子，输入以下命令查看该脚本的使用方法：
generate_glide_grids -h
Usage:
$SCHRODINGER/utilities/generate_glide_grids [options]
Description:
Generates Glide grids based on the specified options.
Box center must be specified as either x,y,z coordinates (-cent_coor
option), ligand ASL (-lig_asl), or by residues ASL (-res_asl).
Ligand ASL and residues ASL are equivalent, except that with the ligand ASL
the matching atoms are removed before generating the grids.
Constraints string is formatted by:
label1#atomnum1:label2#atomnum2:label3#atomnum3 ... etc.
#### Input File ####
To generate more than one grid, an input file can be specified. The input
file should contain a line for each grid. Each line should contain command
arguments required to run that job.
For example, the input file can be as follows (CSV format):
rec_file,cent_coor,hbond_cons,lig_asl,res_asl
structure1.mae,"1.23,2.32,1.54",hbond1#493:hbond2#1,,
structure2.mae,,"mol.num 1",
structure3.mae,,,"res.num 101,102"
*Note: Number of elements in each grid line must match the number of elements
in the header
###################
The grid generation jobs will be run consecutively (i.e. can't be run in
parallel).
Options:
-v, -version Show the program's version and exit.
-h, -help Show this help message and exit.
-rec_file REC_FILE Receptor structure path.
-cent_coor CENT_COOR Coordinates of the box center in format 'X,Y,Z'
-lig_asl LIG_ASL ASL for atoms that are to be used to determine the box
center. These atoms will be removed before generating
grids.
-res_asl RES_ASL ASL for atoms that are to be used to determine the box
center. The atoms will not be removed.
-flex_asl FLEX_ASL ASL defining flexible receptor atoms. NOTE: If ligand
is being removed, this ASL may no longer match the
same atoms.
-inner_box INNER_BOX Inner box size. (default 10)
-outer_box OUTER_BOX Outer box size(default 30.0 if -lig_asl was not
specified. If it was, then is derived from the ligand
size).
-hbond_cons HBOND_CONS
String of colon-separated H-bond constraints to use.
Each 'constraint' is a string of 'label#anum'.
Example:
'label1#atomnum1:label2#atomnum2:label3#atomnum3'
-vscale VSCALE Receptor van der Waals radius scaling factor. (default
1.0).
-ccut CCUT Receptor van der Waals partial charge cutoff. (default
0.25)
-forcefield FFIELD Forcefield to be used. If no forcefield is given, the
default OPLS forcefield will be used.
-j JOBNAME Job name to use.
-verbose Print debug output.
-write_in Write the Glide *.inp file, but do not run jobs.
Job Control Options:
-LOCAL Do not use a temporary directory for job files. Keep
files in the current directory.
Job Control Options:
-HOST Run job remotely on the indicated host entry.
-WAIT Do not return a prompt until the job completes.
-NOLOCAL Use a temporary directory for job files.
-D, -DEBUG Show details of Job Control operation.
-NOJOBID Run the job directly, without Job Control layer.
这里有些比较常用的命令，如“-rec_file”用来指定输入的文件；“-lig_asl”和“-res_asl”可用来指定生成对接盒子中心原子的ASL，区别在于使用“-lig_asl”会在输出对接盒子文件之前去掉所选原子，而“-res_asl”则会保留所选原子；比如以原配体所在位置为中心生成对接盒子，就意味着是否去掉原配体分子。
可以通过其他命令调整对接盒子的大小、氢键限制、柔性残基等，大家可自行尝试。此外，输入的文件支持.csv文件，相当于提供给generate_glide_grids的参数文件；这里笔者就以输入.csv文件为例：
在文件夹中新建Excel文件，输入以下内容：
第一列指定文件名称，这里为准备好的蛋白-配体复合物的结构文件；第二列指定配体的ASL，这里指定为非蛋白上的原子并且限制原子的数目在10~130之间以排除水分子、金属离子等；
之后将文件另存为.csv格式文件即可，本例中为“Grid.csv”；然后在Schrodinger Power Shell中输入以下命令即可：
generate_glide_grids Grid.csv
等待计算完成后，生成的对接盒子文件会保存在当前的路径：
之后就可以将这些文件作为Glide分子对接的输入文件进行反向分子对接了，当然，可以将很多蛋白质分子进行处理，作为靶标预测的数据库使用是非常不错的！
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