[AMBER] Help needed on MMPBSA for a system with different protonation states in free & bound forms, using multiple trajectory protocol

From: Shailesh Pandey <shaileshp51.gmail.com>
Date: Sat, 16 May 2015 16:48:42 +0530

Dear Amber Users,

I am trying to use MMPBSA.py with multiple trajectory protocol for
estimation of binding free energy of a ligand to its receptor. But in
binding site of receptor(a protein kinase) a histidine is predicted by
PROPKA3.0 to have different protonation state in free and bound states with
apo and holo crystal structures respectively. Due to this MMPBSA.py fails
to detect receptor and ligand residues even if I provide it explicity in
the mmpbsa.in file.

content of mmpbsa.in is as below
Input file for running PB and GB
   startframe = 1, endframe = 999999, interval = 20, verbose=1,
   entropy = 0,
  igb=2, saltcon=0.001,
  istrng=0.001, radiopt=0, inp=1, scale = 2.0, fillratio = 4.0,

I used command as below to invoke MMPBSA.py
$AMBERHOME/bin/MMPBSA.py -O -i mmpbsa.in -o FINAL_RESULTS_MMPBSA.dat \
-cp ../02.leap/com.gas.leap.prmtop \
-rp ../02.leap/rec.gas.leap.prmtop \
-lp ../02.leap/lig.gas.leap.prmtop \
-y ../04.ptraj/com.stripfit.mdcrd \
-yr ../04.ptraj/rec.stripfit.mdcrd \
-yl ../04.ptraj/lig.strip.mdcrd

File "/home/shailesh/soft/amber14/bin/MMPBSA.py.MPI", line 94, in <module>
  File "/home/shailesh/soft/amber14/bin/MMPBSA_mods/main.py", line 608, in
    self.normal_system.Map(INPUT['receptor_mask'], INPUT['ligand_mask'])
  File "/home/shailesh/soft/amber14/bin/MMPBSA_mods/parm_setup.py", line
242, in Map
    "this is not the case.")

Checking in the parm_setup.py, line 242, I found that, this section of code
expects, complex residue sequence to be same as (receptor + ligand)
sequence, but if protonation states are different for any of residue in
free & bound forms, then this condition will never be satisfied, because
diiferent residue names are used for different protonation states.

So, I made a copy of the original receptor prmtop as say
temp_receptor.prmtop and edited its RESIDUE_LABEL section to match
RESIDUE_LABEL section of complex.prmtop

Now trying MMPBSA with temp_receptor.prmtop, It passes this section but
gets caught at charge-cosistency check and error is as below:

File "/share/apps/amber14/bin/MMPBSA.py.MPI", line 94, in <module>
  File "/share/apps/amber14/bin/MMPBSA_mods/main.py", line 609, in
  File "/share/apps/amber14/bin/MMPBSA_mods/parm_setup.py", line 924, in
    (i + 1))
PrmtopError: Inconsistent charge definition for atom 80!

As it is obvious to have different charges for residue's atoms with
different protonation state in free & bound form.

Has anyone faced such things earlier, what can be ways to solve it.


Is there a way to skip prmtop consistency check ??

Any help/suggestion in this regard is highly appreciated.

Thanks !!!

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Received on Sat May 16 2015 - 04:30:02 PDT
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