Hi Junmei,
Thanks again for your response. Sorry about the delay on my part - I just
came back from vacation.
I do think that a new atom type should be introduced for nitrogens in fused
aromatic rings. As I said, it seems wrong for tetrahedral N parameters to
be used for a planar N, expecting that improper dihedral parameters will
force the molecule into a planar conformation. I hope this can be fixed in
future version of GAFF.
In the meantime, because my molecules are all rigid and I simply want the
conformations to be correct, I will change the dihedral parameters so that
the molecules are planar.
Thanks,
Gabriel
On Tue, Sep 28, 2010 at 8:38 AM, Junmei Wang <Junmei.Wang.utsouthwestern.edu
> wrote:
> Hi, Gabriel
> I did some minimization for the two molecules. Here are the details
>
> (1) generating BCC charges (antechamber -fi mol2 -fo prepi -i input -o
> input.prepi -c bcc -nc 1)
> (2) finding missing force field parameters for imidazothiazllium
> (3) conducting gas-phase minimization
>
> The following is the input
>
> Minimization
> &cntrl
> igb = 0, ntb = 0, ntpr = 25, ntwx = 100, ntp = 0,
> cut = 999.0, ntc = 1, ntf = 1,
> imin = 1, maxcyc = 1000, ntmin = 1, drms = 0.05,
> ibelly = 0, ntr = 0, ncyc = 10,
>
> /
> (4) generating the mol2 files for the minimized structures (top2mol2 -p
> prmtop -c rst -o mol2)
>
> And I found both minimized structures are planar.
>
> I then modified the input a little bit, change drms = 0.05 to drms = 0.01,
> I found the minimized structure of imidazopyridine is still planar, but
> that of imidazothiazllium bends.
>
> I then modified the improper dihedral angles (changed from 1.1 to 5.6 for
> the following two parameters)
> in the frcmod file generated by parmchk
>
> na-na-cc-ss 5.6 180.0 2.0
> cc-cc-na-cc 5.6 180.0 2.0
>
> I got the planar conformations for both molecules in both minimization
> protocols.
>
> So my suggestion is to use a little bit less stringent convergence criteria
> or to use a larger force
> constants for the improper dihedral angles (To me, it is OK since the
> improper dihedral angles are
> mainly used to penalize the off-planar conformations and the force
> constants of improper dihedral angles
> in GAFF were not derived stringently).
>
> In GAFF, X-ca-na-X was derived using the model compound of phenol pyrrole.
> It is probably a good
> idea to introduce a new atom type just for the N in the fused rings. This
> issue will be taken care in
> the next version of GAFF.
>
> All the best
>
> Junmei
>
>
> ------------------------------
> *From:* grocklin.gmail.com [grocklin.gmail.com] on behalf of Gabriel
> Rocklin [gabriel.rocklin.ucsf.edu]
> *Sent:* Monday, September 27, 2010 11:29 PM
> *To:* Junmei Wang
> *Cc:* case; amber.ambermd.org; David Mobley
> *Subject:* Re: Aromatic C and N atom type problems in Antechamber
>
> Dear Junmei,
>
> Thanks for your response. It was very helpful. I still have a few
> questions to try to explain the strange results that I'm getting.
>
> First, I realize now that I wasn't using the latest version of
> Antechamber. I was using Antechamber 1.27 instead of the version included
> in AmberTools 1.4. I've now parameterized my molecules using Antechamber in
> AmberTools 1.4, and now I get the same atom types as what you sent me. This
> seems to have fixed the problem I observed where aromatic atoms would be
> typed as nh, c2, etc. You've also explained to me that the 'na' atom types
> observed in imidazole, pyrrole, etc are actually correct, so I'm not worried
> about seeing this now. However, I still am getting molecules with
> conformations that seem to be incorrect. Perhaps this is a parameter
> problem rather than an atom typing problem?
>
> There are at least two parameters that I think are causing problems.
>
> The first is the torsion:
> X -ca-na-X 4 1.200 180.000 2.000
>
> If ca is a pure aromatic carbon, and na is a planar aromatic nitrogen,
> why is the barrier to rotation so weak here (1.2 kcal/mol)? This comes up
> when I parameterize imidazopyridinium. In my first email, I sent a mol2
> file for imidazopyridine. When I parameterize this, the atoms bridging the
> ring are typed as cd and na, and have a rotation barrier of 6.8 kcal/mol.
> However, in imidazopyridinium (attached), the atoms are typed as ca and na,
> so the rotation barrier is only 1.2 kcal/mol. This allows the two fused
> rings to fold against each other rather than staying planar. I've attached
> an example conformation (pdb) that I've gotten from doing a vacuum
> simulation of this molecule using the GAFF parameters. Is there a parameter
> problem here, an atom typing problem, or neither? Why should
> imidazopyridinium have such a different barrier than imidazopyridine?
>
> The second problem is with angles. Going back to imidazopyridine, when I
> parameterize this using AmberTools 1.4, all of the carbons around the
> ring-bridging nitrogen are typed cc, and the bridging nitrogen is typed na.
> This is also true in the file imidazopyridine.prepi that you emailed me,
> although your molecule seems to have added some phenyl groups. The cc-na-cc
> angle in gaff.dat (as well as in the imidazopyridine.frcmod that you sent
> me) is specified as:
>
> cc-na-cc 68.940 109.900
>
> This is basically a tetrahedral angle, even though all three of these
> atom types are supposed to be planar and aromatic. So, the nitrogen which
> fuses the rings attempts to be tetrahedral, which results in the rings
> folding up against one another (partially) rather than the entire molecule
> staying flat.
>
> One molecule that particularly suffers from this angle problem is
> imidazothiazolium. This also contains a cc-na-cc angle despite being fully
> aromatic (I think?) and results in bent conformations. I've attached a mol2
> file and pdb file from a vacuum simulation of this molecule using GAFF
> parameters and the bending of the aromatic rings is very obvious. Is there
> something wrong with these aromatic angle parameters?
>
> Thanks for your earlier reply and I hope we can identify what is
> happening here and fix a problem if there is one.
>
> Finally, I am going to be on vacation from 9/28 until 10/15. I still
> want to get this issue resolved, but I won't be able to reply to emails in
> that time period. If you identify a problem or can explain to me to what's
> happening, I'll look at it as soon as I get back.
>
> Thanks,
> Gabriel
>
> Gabriel Rocklin
> UCSF Shoichet/Dill Labs
>
>
>
> On Wed, Sep 22, 2010 at 8:56 AM, Junmei Wang <
> Junmei.Wang.utsouthwestern.edu> wrote:
>
>> Dear Gabriel,
>>
>> Thank you very much for your question. The following is my explanation.
>>
>> In GAFF, we have several types for aromatic/aliphatic properties, from AR1
>> (pure aromatic, such as benzene and pyridine), to AR2 (planar systems other
>> than AR1), to ... AR5 (pure aliphatic systems). Most heterocyclic systems,
>> such as pyrrole, imidazole and the five memberred rings of indole and
>> 4-azaindole (excluding the bridge/fused atoms), belong to AR2.
>>
>> When the protonation state changed, the atom type must also be changed.
>> For example, the pyridine N is 'nb' if deprotonated and 'na' if protonated.
>> Otherwise, there is no way to use generic torsional angle terms (the
>> multiplicities are different for 'nb' and 'na'). By the way, 'na' is the
>> planar nitrogen with three bonded atoms.
>>
>> Did you use the new atom type definition file? In the new version, no 'c2'
>> atom type existing any more for AR2 atoms. The 'c2' atom type is replaced
>> with either 'cc' or 'cd' and a much higher rotational barriers are used in
>> GAFF for torsional angles involved 'cc' and 'cd'.
>>
>> Do you have probamatic molecules that produce wrong/weird conformation in
>> your free energy calculations? If you have some, could you please send them
>> to me? I would like to figure out what is the problem.
>>
>> I have generated the mol2, prepi and frcmod files for the molecules you
>> mentioned in your last email. Please let me know if you get a different
>> result.
>>
>> Best
>>
>> Junmei
>>
>>
>>
>>
>> ------------------------------
>> *From:* grocklin.gmail.com [grocklin.gmail.com] on behalf of Gabriel
>> Rocklin [gabriel.rocklin.ucsf.edu]
>> *Sent:* Monday, September 20, 2010 3:20 PM
>> *To:* Junmei Wang; case; amber.ambermd.org; David Mobley
>> *Subject:* Aromatic C and N atom type problems in Antechamber
>>
>> 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
>>
>>
>> ------------------------------
>>
>> UT Southwestern Medical Center
>> The future of medicine, today.
>>
>
>
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Received on Mon Oct 25 2010 - 15:30:02 PDT
