I took the CHARMM parameters I generated for the lysine-branched chelator (charges, bonds, angles and dihedrals), and inserted the metal assigning it a dummy charge of +3. I restrained only the metal-chelator bonds and angles to values that were generated to reproduce experimental NMR values in the paper:
Computational approaches to the study of some lanthanide (III)–polyazamacrocyclic chelates for magnetic resonance imaging
Elsa S. Henriques, Margarida Bastos, Carlos F. G. C. Geraldes, Maria João Ramos
International Journal of Quantum Chemistry (Impact Factor: 1.31). 03/1999; 73(2):237 - 248. DOI:10.1002/(SICI)1097-461X(1999)73:2<237::AID-QUA17>3.0.CO;2-W
Now, in that paper they minimise both conformers with the parameters and demonstrate a 3 kcal/mol energy difference, consistent with experiments. This, to them, is a way of deciding on the validity [sic] of their parametrisation. I know we're far away from the CHARMM philosophy here.
I finally found some time to look over the structures and download and read the paper:
One of the reasons why I was so adamant on 3D structures was that I wanted to know if there was any chance that part of the metal would be solvent-exposed. Based on the current information, the answer to that question seem to be "reversible binding of the water to the metal can and does occur". This largely invalidates the proposal of using dummy L-J parameters and charges.
Although the methodology in the paper is different from our standard recommendations, we already established that the standard approach doesn't apply to this system for several reasons. Keeping this in mind, Henriques et al.'s approach seems to be quite solid, and I would recommend you just transfer as much as you can from their paper. The only thing I would be careful of is the "capping water"; since it has such exceptional charges, I would introduce a weak restraint (using CHARMM's NOE functionality) that is zero in the range of normal interaction distances and comes into effect when the water starts dissociating. The idea is to prevent that abnormal water from drifting off into the solvent and wrecking havoc.
For the reference of other people who come across this thread, I would like to repeat that I almost always recommend against using 3rd party parameter sets from the literature, especially if they don't follow standard procedures. It's just that for this very exceptional case, the standard procedure doesn't apply, and the literature approach is of a rarely seen quality. In fact, for this system, I cannot come up with a significantly better alternative approach than what Henriques et al. did (bar a 6-month parametrization project).
Edit: oh, for the record, the Henriques et al. charges do show some clear signs of overfitting and the L-J parameters would qualify as "poorly validated", but for a system like this, both flaws are very hard to avoid, and since it's conformationally quite rigid and we're not transfering the charges to a significantly different molecule, I think we can get away with it for this once.
ok, I had initially tried to mix their parameters with mine, but I was not confident it would work.
I found that my CHARMM parameters with restraints on the metal, a +3 charge on the metal, and the LJ parameters from Henriques, were able to reproduce the crystal structure of DOTA to a good extent (no data shown, I'm still working on processing all the data). The backbone RMSD of the DOTA in solution is 0.5 A rel. to the crystal, and I was otherwise going to consider it sufficient to start simulating.
The big problem with the Henriques paper is that they do not give parameters except for the Metal - Ligand interactions (so, bonds and angles to the metal). The partial charges are not at all clear how to use (no sign given).
I have found more sucess with this approach than with the scrambled mix I got by taking those Henriques et al. parameters and mixing them with mine...
I don't think the +3 charge on the metal is very realistic. Highly charged entities transfer a lot of their charge to their immediate surroundings in bulk phase, and this has a relevant effect on how these immediate surrounding interact with other stuff. Also, what do you mean with "no sign given"? I'm looking at the RESP columns in table IV and don't see anything that would preclude usage.
As for the bonded parameters, they probably transfered a lot from the CHARMM22 protein FF. One thing you could do is e-mail the corresponding author asking for the force field files (just google her; she's still leading a research group). That would leave a lot of guesswork out of the process, and explaining out of your future papers.
Well, I tried adding up the RESP column, to me it is not clear how I would achieve an overall integer value with their charges (I can't figure out which ones are + and which ones are -).
I already contacted her a while ago, this paper is about 15 years old, I doubt they still have the data around.
If the CHARMM parameters for the chelator with a restraint on the metal can yield an ensemble of structure in the bulk that reproduces the crystal structure, is this not better than mixing parameters? I have no guarantee the author still has the values they used with RESP (which is from the AMBER philosophy?).
Anyhow, thanks for your help, much appreciated!
Otherwise, I will have to give the CHARMM values another try.
I think there might be something wrong with the pdf viewer you're using or perhaps with the fonts you have installed on your system; as you can see in the attached crop from a screenshot, I'm seeing positive and negative values.
If you cannot reach the group leader, maybe try the first author; group leaders are often very busy. The fact that it's 15 years ago is not necessarily a problem; I still have copies of my very first molecular modeling work, dated 1999-2000.
Originally Posted By: chemist
If the CHARMM parameters for the chelator with a restraint on the metal can yield an ensemble of structure in the bulk that reproduces the crystal structure, is this not better than mixing parameters?
I'm more concerned about how it interacts with water, which they seem to have done some effort to get right.
Originally Posted By: chemist
RESP (which is from the AMBER philosophy?).
The big problem with this molecule is the charges. Both RESP and the CHARMM-style water interactions have issues with buried atoms. In CHARMM, we work around these issues by splitting up the system, and then transfering charges when re-assembling, but here, you cannot do that because the +3 ion in the middle that is not completely shielded from solvent changes everything. If it would be possible to do a large number of water interactions, then it would in theory (though often not in practice) be possible to resolve the effect of the buried charges. However, the CHARMM methodology calls for constraining oneself to relevant water interactions, of which there are not enough. In this respect, the many ESP samples used in RESP have a definite advantage. Yes, the charges will not be balanced against the other parameters. However, AMBER also uses TIP3P water and the Lorentz-Berthelot combining rules, so they likely won't be totally outrageously catastrophical (compared to more exotic nonbonded models like MMFF94). Usually, I vehemently oppose using RESP charges (or the Merz-Kollman charges we used to use as an initial guess before the CGenFF program was ready) because there's always a way to get charges that are more likely to be CHARMM-compatible with minimal to moderate effort. However, in this particular case case, I don't see how I would do that, so the (likely poorly balanced) charges will have to do in a pinch. It can't possibly be worse than setting the metal to +3 and using transfered chrges for the atoms that bind to it (and are also solvent-exposed).
Last edited by Kenno; 04/02/1406:49 PM. Reason: added attachment, reference to Merz-Kollman, and last sentence.
Is this by any chance Firefox' built-in pdf viewer? Because I don't like that one. Apart from occasional display issues, its performance is horrible. The only good thing about it is that it gets rid of the gaping security hole that is the Adobe PDF plugin.