Dear Junmei and others,
I am trying to parameterize various heterocyclic compounds using
Antechamber, and I'm getting strange results. Nitrogen and Carbon atoms
that I think should be classified as aromatic are being classified as
non-aromatic sp2. This creates a problem for free energy calculations
because the non-aromatic atoms have very weak dihedral parameters associated
with them which allows incorrect conformations.
I can't trace all the problems I'm seeing to a single issue, so instead I'll
list several. In all the examples, I'm using the version of
ATOMTYPE_GFF.DAT that you send me in February, linked below (is there
something newer?)
http://archive.ambermd.org/201002/0314.html
First I have some questions about pyrrole and imidazole.
1) When I parameterize pyrrole.mol2 doing:
antechamber -f pyrrole.mol2 -fi mol2 -o pyrrole.prepi -fo prepi
The nitrogen is classified as type 'na', which is described in GAFF.dat as:
"Sp2 N with three connected atoms" which is a non-aromatic atom type.
Shouldn't this be classified as aromatic? (Pyrrole isn't actually a
molecule I'm interested in, but this is one of the most basic cases of the
issue I can find).
2) When I parameterize neutral imidazole.mol2 in the same way, the Ns have
two different atom types. The deprotonated nitrogen is recognized as 'nc',
which GAFF.dat says is aromatic ("Sp2 N in non-pure aromatic systems")
whereas the protonated nitrogen becomes 'na', again not aromatic. If there
were a substituent coming off this nitrogen (or both nitrogens, in an
imidazolium derivative) these would be parameterized such that they could
bend significantly out of plane of the ring because the N was not classified
as aromatic. Should they be parameterized this way or is the atom type
assignment wrong?
Now some issues with fused ring systems...
3) Indole. The N in indole is classified as "na". Shouldn't this be
aromatic?
4) Imidazopyridine vs Indole. This is the kind of fused ring system that
I'm interested in and where I see real problems. In Imidazopyridine, N1
(the same N as in Indole, except now deprotonated) is recognized as aromatic
and classified as 'nc'. But the N bridging the ring systems is the
non-aromatic "na". Several carbons also change atom type. In Indole, all
of the carbons are 'ca', 'cc', or 'cd' (all aromatic). In Imidazopyridine,
some carbons switch to 'ce', 'cf', and 'c2', none of which are aromatic.
The "na" nitrogen bridging the rings means that the two rings actually have
the flexibility to bend toward each other, rather than the entire molecule
staying planar.
5) 4-azaindole vs 4-azaindolium. In 4-azaindole, everything except the
protonated nitrogen is aromatic. As far as I know, it should be aromatic,
but this seems like the same problem as above. However, in 4-azaindolium
(both nitrogens protonated), several carbons become nonaromatic (c2). One
of the nitrogens even becomes classified as NH ("Amine N connected one or
more aromatic rings") which must be because it itself is not recognized as
aromatic.
The above nitrogen issues seem to all come from any nitrogen being bonded to
three atoms not being recognized as aromatic. However, this doesn't seem to
be the full extent of the problem, because even the carbons in
Imidazopyridine and 4-azaindolium become non-aromatic. My main concern in
all of this is the torsional parameters because I don't want my aromatic
fused rings to be folding in on each other if they aren't supposed to be.
I've attached mol2 files of all of these molecules to see if you can
reproduce what I'm seeing, and in the hope that a fix can be found.
Thanks,
Gabriel Rocklin
UCSF Shoichet/Dill Labs
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Received on Mon Sep 20 2010 - 13:30:04 PDT
