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charge optimization for a sulfoximine molecule
#30550 08/23/12 02:07 AM
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Hi,
I am optimizing the parameters for a sulfoximine molecule (picture attached). I got the guess parameters from parachem. In charge optimization, the MM interaction energies are way off than the QM ones. I was able to get most of MM interaction energies in reasonable agreement with the QM, however O3 charge in the picture is difficult to optimize. I gave it zero charge and neighboring atoms positive charges and still the interaction energy difference is almost -7. I appreciate if there are any suggestions or tricks I could use to get the charges optimized.
NOTE: charges were calculated using HF/6-31G(d) and not scaled since this is a charged molecule.
Also, The MM minimized structure used for charge optimization is the same geometry as the QM global minimum geometry.

The picture of the molecule and the interaction energies before and after optimization are attached.


Thank you

Attached Files
msxn-allwat.jpg (52.43 KB, 458 downloads)
Interactionenergies.PNG (36.61 KB, 460 downloads)
Re: charge optimization for a sulfoximine molecule
biochemist #30561 08/25/12 02:38 AM
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Nice job on the picture and table. smile This is a highly polarized and somewhat crowded molecule, which may explain some of the differences you're seeing. It would be interesting to rotate the water molecule on O3 such that the hydrogen that is not interacting with O3 is pointing the other way (away from the ethyl group instead of towards it), and see how this changes the energy in the QM. Additionally, be advised that O3 has localized lone pairs; it would be interesting to construct a water interaction at the lone pair position that is farthest from the ethyl group for comparison. Finally, let's see the charges you got. Given all that information, I probably can give you some guidance. All I can tell you know is that O2 should have the same charge as O7, that all the hydrogens must be +0.09 , and that the terminal methyl moiety of the ethyl group should be neutral (but this won't solve your problem).

Re: charge optimization for a sulfoximine molecule
Kenno #30578 08/29/12 03:55 PM
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Thank you for your reply and suggestions.

First suggestion: I rotated the water molecule on O3 away from the ethyl group (msxn-allwat-2.jpg)and I was able to optimize the charges and get good agreement between QM and MM interaction energies.(interaction-energies-2.png)

Second suggestion: I constructed a water interaction at the lone pair position that's farthest from the ethyl group(msxn-allwat-3.jpg). The QM interaction energy is +0.2265 (repulsive !!) while the the MM interaction energy is -11.4. This behavior is strange. Anyway, I will go ahead and continue optimizing the missing parameters using the optimized charges in the first suggestion.

Attached Files
msxn-allwat-2.jpg (47 KB, 309 downloads)
interaction-energies-2.JPG (48.09 KB, 307 downloads)
msxn-allwat-3.jpg (45.02 KB, 293 downloads)
Re: charge optimization for a sulfoximine molecule
biochemist #30579 08/29/12 06:06 PM
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  • Rotation of O3 water: this was clearly the right thing to do; judging by the pictures and energies, we eliminated interference from the ethyl group by doing so.
  • The lone pair position looks incorrect in the figure. The lone pair should points out of the P-O-C plane, so that the oxygen with its two covalent bonds and two lone pairs assumes a tetrahedral geometry.
  • Can we see the charges? It's important to check that they're well-behaved.

Re: charge optimization for a sulfoximine molecule
Kenno #30581 08/29/12 07:52 PM
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Please find the attached stream files ( before msxn.str and after charges,bonds and angles optimization msxn7.str). I will fix the lone pair position of the other molecule and see what happens.

Attached Files
msxn7.str.txt (4.15 KB, 334 downloads)
msxn.str.txt (4.37 KB, 346 downloads)
Last edited by biochemist; 08/29/12 07:56 PM.
Re: charge optimization for a sulfoximine molecule
biochemist #30584 08/30/12 06:31 PM
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Oops, it seems like the sulfoximine moiety (which we never considered when creating and testing the atom typing rules) triggers a previously unknown bug. The S atom type should be SG3O2 rather than SG3O3 . This will result in different parameters and charges being assigned by analogy (though the differences in parameter values may not be that big). More importantly, different existing parameters will be used. In particular, the SG3O3 OG2P1 bond is special; SG3O2 OG2P1 should probably work better for your molecule. Also, the CG331 CG321 SG3O2 OG2P1 dihedral is significantly different from CG331 CG321 SG3O3 OG2P1 . The other differences (the CG3[23]1 SG3O[23] OG2P1 angle and CG3[23]1 SG3O[23] bond) will probably have a smaller impact. I'm sorry about this; this is why it's beta. I'll have it fixed in the next release.

EDIT: In the meanwhile, if you post the mol2 file of your molecule, I will run it through a developmental CGenFF version that contains a temporary workaround for this bug.

Now about the charges:
  • The -0.73 on C19 is absurd; this is a clear case of overfitting. It is strongly recommended to stick with the default -0.27 .
  • To improve the transferability of the charges, it would also be recommended to fit the charges under the constraint that C9 should be exactly 0.09 more positive than C13. See RESI MESN in the main CGenFF distribution for a good example. Additionally, both C9 and C13 seem way more negative than could possibly be physically justified.
  • Similarly, S11 is way too positive (which goes hand in hand with the carbons being too negative).
  • C4 also appears to be more negative than it should be.
I think the above points need to be taken care of. Specifically, you want to re-optimize the charges on the C-C-SO-C part while staying reasonably close to the corresponding charges on MESN. In fact, I think you should set C13, C9 and C19 to the exact same values as in MESN, since you don't have target data for them (I assume this because typically, all the interactions with aliphatic hydrogens are repulsive on molecules that have a net negative charge). Similarly, C4 should be set to the value in RESI DMEP and MP_1 (-0.17). As a side note, you might want to get rid of the 3rd decimal in the charges while you're at it. It's not really significant, it looks sloppy, and I've heard that some old versions of some MD programs wouldn't read it correctly.

Note that the above changes - especially the change in atom types but also the big change in charges - may require tweaking the bonded parameters (that's why we do the charges first).

Finally, carefully consider on which conformation you want to optimize the charges and bonds and angles. What is the difference in energy between the gauche (±60°) and trans (180°) conformations of the O-S-N-P dihedral? If the trans conformation were to turn out to be much higher in energy, it will be scarcely populated, and it may be worth optimizing the force field on a gauche conformation instead (provided that the the water interactions are not much more hindered in this gauche conformation). The same goes for the S-N-P-O3 dihedral; consider if it shouldn't be trans rather than gauche. And then there's also the N-P-O-C and N-S-C-C ... What we usually do is pick a reasonably low-energy structure in which the water interaction sites are mostly unhindered, which often (but not always) corresponds to an all-trans or extended conformation. In some extreme cases, we even calculate water interactions on two distinct conformations and make a compromise when optimizing the charges.

Last edited by Kenno; 08/31/12 04:02 PM.
Re: charge optimization for a sulfoximine molecule
biochemist #30599 09/01/12 11:18 PM
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Thank you for this extensive explanation and telling me about this bug. This explains why there were some non missing CHARMM bond and angles with bad agreement with their respective QM ones. I am working now on the new stream file. I am also attaching the .mol2 file of this molecule.

Regarding the conformation I am using, I did mp2/6-31G+(d) on all possible trans-cis dihedral combinations and the conformation I am attaching was the lowest energy one. I will post their pictures and energies and the new stream file later today.

Attached Files
msxn.mol2.txt (1.21 KB, 298 downloads)
Re: charge optimization for a sulfoximine molecule
biochemist #30600 09/02/12 03:28 AM
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Originally Posted By: biochemist
I am also attaching the .mol2 file of this molecule.
And here is the promised .str file. Again, the parameters may not be that much different from what you used as an initial guess.

Originally Posted By: biochemist
Regarding the conformation I am using, I did mp2/6-31G+(d) on all possible trans-cis dihedral combinations and the conformation I am attaching was the lowest energy one. I will post their pictures and energies and the new stream file later today.
The most important is that you thought of doing these calculations at all. A lot of people don't think that far so I got into the habit of questioning everything. In the same vein, please note that a true cis conformation of a bond between two tetrahedral atoms is almost always a maximum (or more correctly, saddle point), in which the QM minimizer may get stuck. Therefore, it is more relevant to do the aforementioned calculations on gauche and trans combinations rather than cis-trans.

Attached Files
msxn.str.txt (4.22 KB, 325 downloads)
Re: charge optimization for a sulfoximine molecule
biochemist #30604 09/03/12 04:54 PM
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I am sorry. I didn't describe how I did the conformational search correctly.

I did mp2/6-31G+(d) optimization on all possible trans-cis dihedral combinations and the conformation I am attaching was the lowest energy optimized conformation.

Thank you for providing me the stream file. I am optimizing the charges and I will post it later.

Re: charge optimization for a sulfoximine molecule
biochemist #30610 09/04/12 07:17 PM
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I understood that. As I mentioned in my previous post, the problem is that QM minimizers (aka. optimizers) have a very strong tendency to get stuck in saddle points, and the only way to know this for sure is to follow the optimization with a frequency calculation and check for negative frequencies (although in practice, if you make sure that your input conformation is asymmetric, you'll almost never get stuck in a saddle point).

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