Non-natural residue parameterization with GAFF

  1. Use Gaussian to minimize the structure and calculate the resp charges of every atom.
  2. Open the output file with Gaussian View and save the structure as lig_full.mol2. Open the exported mol2 structure with Discovery Studio. Remove the extra atoms and make sure the overall charge of the molecule is zero. Save the structure as lig.mol2
  3. Use antechamer to convert the format
    Antechamber -fi mol2 -fo ac -i lig.mol2 -o lig.ac -at gaff -rn LIG
  4. In the previous step, gaff atom type has been applied to the new ligand. Check the automatically assigned atom type and make sure they are right. See the website of gaff for reference: http://ambermd.org/antechamber/antechamber.html
  5. Convert to .prepi format
    Prepgen -i lig.ac -o lig.prepi -f prepi -m lig_mainchain -rf lig.res
  6. Double check the atom charges and atom types.
  7. Check missing force field parameters
    parmchk -i lig.prepi -f prepi -o lig.frcmod -p gaff.dat
  8. Fill the missing force field parameters in lig.frcmod, and search references to find a right value for them. Or perform Gausssian calculation, which is much more complicated.
  9. Generate .lib file for tleap.
    xleap
    loadamberprep lig.prepi
    loadamberparams lig.frcmod
    saveoff lig lig.lib
  10. Change the residue type in lig.lib file to ā€œpā€
  11. Edit and run tleap.in to generate input files for AMBER MD. If there is any error in the logfile, fix it.

Example of tleap.in

source leaprc.ff99SB
source leaprc.gaff
loadamberparams TBM.frcmod
loadoff TBM.lib
loadamberparams LIG.frcmod
loadoff LIG.lib
VB = loadPdb uPA-pep-TBP.pdb
bond VB.247.SG VB.262.C01
bond VB.252.SG VB.262.C05
bond VB.259.SG VB.262.C08
set VB.247.SG charge -0.1629
set VB.252.SG charge -0.1629
set VB.259.SG charge -0.1629
remove VB.262 VB.262.H12
remove VB.263 VB.263.H
bond VB.262.C09 VB.263.O
remove VB.198 VB.198.HG
remove VB.198 VB.198.OG
remove VB.263 VB.263.H44
bond VB.198.CB VB.263.O11
addions VB Cl- 0
addions VB Na+ 0
solvatebox VB TIP3PBOX 10
setBox VB centers
saveoff VB ./st1.lib
savepdb VB ./st1_solvated.pdb
saveAmberParm VB ./st1.prmtop ./st1.inpcrd
quit