Computational Drug Discovery and Design

In the next step, use tleap to create topology and coordinate

files for the ligand. The following script shows an example of tleap’s

input:

source leaprc.ff03 (for basic definitions)

source leaprc.gaff (for the ligand)

set default PBradii mbondi2

loadamberprep lig.prep (antechamber-generated file)

loadamberparams lig.frcmod (parmchk-generated file)

check LIG (there should be no error messages)

saveamberparm LIG lig.prmtop lig.inpcrd (save the ligand topology)

savepdb LIG lignew.pdb (use this file to add ligand to the receptor)

quit

Note that we are using the same residue name (LIG) as the one

we defined for antechamber (seeNote 10).

2. Prepare a receptor–ligand complex by combining protein and
   ligand in a single PDB file (e.g., “complex.pdb”). Copy the
   ligand’s PDB file at the end of the receptor’s PDB file. Attri-
   bute a unique chain identifier to the ligand’s residues. Insert
   TER records after each molecule. Then, run tleap on the
   following script:

source leaprc.ff03

source leaprc.gaff

set default PBradii mbondi2

loadamberprep lig.prep

loadamberparams lig.frcmod

mol=loadpdb complex.pdb

# add modifications, such as disulfide bonds, if any

check mol

# the unit should be OK, except warnings about close

contacts.

# They will be removed by subsequent energy minimizations.

saveamberparm mol cpl.prmtop cpl.inpcrd (save topology)

savepdb mol cpl.pdb

# saves newly assigned residue numbers, protons included

quit

If the script terminates without errors, the complex structure is

correct. See the contents of the output cpl.pdb file for newly

assigned residue numbers (containing protons). Solvate the system

and add charge neutralizing ions if necessary, by completing the

above script with the solvatebox and addions commands, as dis-

cussed in Subheading3.2 (seeNote 11). This will produce topol-

ogy files for the whole system, with names such as sys.prmtop, sys.

inpcrd and sys.pdb.

166 Gre ́gory Menchon et al.