[AMBER] Prmtop for protein + 2 identical ligands has wrong dihedral parameters for the second ligand. LEaP bug?

From: Mariano Curti <mcurti.iciq.es>
Date: Fri, 18 Sep 2020 16:41:26 +0200

Dear all,

I've found unexpected behavior from LEaP (Amber 18), thus would be
grateful if you help me determine whether this is a mistake from my
part, or a bug in the program.

I'm using MCPB.py to build parameters for a metal-containing ligand that
is covalently attached to a protein. When using only one of these
ligands, everything works well. However, when I include two ligands,
while LEaP builds the dihedral parameters list correctly for the first
ligand, it (wrongly) includes additional dihedrals for the second ligand.

A reduced tLEaP input that reproduces this behavior is as follows. Note:
I have derived the metal-related parameters using MCPB.py for one
ligand, but the second is identical, so I use the same set. In this
example the two first residues are the first ligand, while residues 3
and 4 are the second ligand. I omitted the protein since it does not
affect this problem.

source leaprc.gaff
addAtomTypes {
         { "M1"  "Zn" "sp3" }
         { "Y2"  "N" "sp3" }
         { "Y3"  "N" "sp3" }
         { "Y4"  "N" "sp3" }
         { "Y5"  "N" "sp3" }
ZN1 = loadmol2 ZN1.mol2
PZ1 = loadmol2 PZ1.mol2
loadamberparams PPZ.frcmod
loadamberparams complex_mcpbpy.frcmod
mol = loadpdb complex.pdb
bond mol.1.ZN mol.2.N
bond mol.1.ZN mol.2.N1
bond mol.1.ZN mol.2.N2
bond mol.1.ZN mol.2.N3
bond mol.3.ZN mol.4.N
bond mol.3.ZN mol.4.N1
bond mol.3.ZN mol.4.N2
bond mol.3.ZN mol.4.N3
saveamberparm mol complex.prmtop complex.inpcrd

When looking at the resulting prmtop, I notice that there are extra
dihedral parameters (with non-zero force constants) involving the metal
of the second ligand. At the end of the day, this seems to result in
weird MMGBSA results.

Now, if I follow the same steps, but this time treating the two ligands
as different (i.e. renaming the residues so LEaP thinks they are
different), I get the expected prmtop, with matching dihedral parameters
for both ligands.

My question is, then: am I doing something wrong, or this is a bug in
LEaP? I would be happy to provide any necessary additional information
or files.

Many thanks in advance!

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Received on Fri Sep 18 2020 - 08:00:02 PDT
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