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Having spoken with a group member who derives charges a lot, that is
probably a reasonable deviation.  I'll try to find the data for the charge
derivation that was done here.  If I can find it, I can get you a more
solid statistics-based answer.


On Wed, Aug 8, 2018 at 11:42 PM Lee-Ping Wang <[log in to unmask]> wrote:

> Hi there,
>
> I’m writing back with an update - we tried a few modifications to the
> procedure I described to derive the sialic acid charges.  The “original”
> procedure is described earlier in the thread, and each test involves
> changing only one thing in the whole procedure.  Here are some RMS errors,
> comparing the charges we derived vs. the charges in GLYCAM.
>
> - RMSE vs. GLYCAM charges -
> Our “original” procedure: 0.0572
> Ring dihedrals constrained (in addition to exocyclic) in the geometry
> optimization step: 0.0580
> Adding diffuse functions (6-31+G*) in the geometry optimization and ESP
> calculation steps: 0.0807
> Using ROH as the aglycon (instead of OME): 0.0550
>
> From these tests, I think that adding diffuse functions actually increases
> the difference vs. the GLYCAM charges, and the other changes only make a
> small difference.  I’m still not sure what is preventing us from
> reproducing the GLYCAM charges more closely, but perhaps this level of
> error is acceptable for proceeding with our research.  Please let me know
> if you have additional ideas.
>
> Sincerely,
>
> - Lee-Ping
>
> On Jul 26, 2018, at 6:11 PM, Lee-Ping Wang <[log in to unmask]> wrote:
>
> Hello Lachele,
>
> Thank you very much for your feedback.  I was traveling for a few days,
> sorry for the slow response.  The large distortions in the ring (after
> constrained energy minimization at HF/6-31G*) are quite common for this
> system.  I expect they may become even more common if we add more chemical
> substitutions.
>
> I will try two approaches and get back to you with results: (1)
> Constraining the ring dihedral angles in addition to the exocyclic ones
> when doing energy minimization; and (2) including diffuse functions in the
> basis set when minimizing and computing the ESP.
>
> Sincerely,
>
> - Lee-Ping
>
> On Tue, Jul 24, 2018 at 10:33 PM Lachele Foley <[log in to unmask]> wrote:
>
>> In the course of an MD simulation, it is common to encounter structures
>> that are not at a local minimum.  If a structure is flexible - that is, if
>> its energy landscape is 'flatter' - then it might stray quite far from
>> local minima.  I am not familiar with the finer details of sialylate's
>> ring-puckering prefeences, but its electronic structure causes it to have
>> other interesting conformational proclivities, notably increased
>> flexibility in the psi dihedral (the exo-anomeric effect).
>>
>> In the image you show, I suspect that the main drivers for the
>> conformational change are attraction between the H5N and the carboxylate
>> and repulsion between the regions of high ESP in the O5N and O4.  In this
>> case, it might be more realistic to find a way to sample conformations more
>> similar to the un-minimized structure.  This is especially so if structures
>> such as these account for a reasonable fraction of the structures from your
>> simulations.  If these changes are relatively rare, it might not make a lot
>> of difference.
>>
>> Diffuse functions are needed for proper charge calculations in charged
>> species.  I don't know enough to say how strong their effect is on
>> geometries in these systems.  You should take a look at the papers by Matt
>> Tessier (for examples, see link below).  He did a lot of the work with
>> NeuNAc.  Others in the group might also have opinions.
>>
>> https://scholar.google.com/scholar?hl=en&as_sdt=0%2C11&q=matthew+tessier+sialic&btnG=
>>
>>
>> On Tue, Jul 24, 2018 at 12:48 AM Lee-Ping Wang <[log in to unmask]>
>> wrote:
>>
>>> Hello Xiaocong,
>>>
>>> The use of different basis sets is one possible source of the
>>> difference.  I based the choice of using 6-31G* on the following:
>>>
>>> From the 2007 GLYCAM paper, there is the quote “For each of these
>>> snapshots partial charges were calculated by fitting to the HF/6-31G* MEP.
>>> Prior to the charge calculations, each structure was optimized at the
>>> HF/6-31G* level, with the rotatable exocyclic bonds constrained to their MD
>>> conformations.” In addition, the RED server also uses this basis set to
>>> derive GLYCAM charges:
>>>
>>> # RESP-C2:  HF/6-31G(d)//HF/6-31G(d)                              CHELPG
>>> algo.    1 RESP fit(*1)  qwt=.0100
>>> #   Used in the Glycam FF
>>>
>>>
>>> On the other hand, the 2007 paper also says "The HF/6-31G* level of
>>> theory was employed for neutral fragments, whereas for anionic molecules
>>> diffuse functions were added.”  The basis set you mentioned, 6-311+G**,
>>> differs from 6-31G* in several ways – not only does it add diffuse
>>> functions, but also a valence shell on the heavy atoms and polarization
>>> functions on the hydrogens.  Is there a better reference for the charge
>>> derivation procedure that you could point me to?
>>>
>>> Thanks a lot,
>>>
>>> - Lee-Ping
>>>
>>> On Jul 23, 2018, at 8:33 PM, Xiaocong Wang <[log in to unmask]> wrote:
>>>
>>> Hi Dr. Wang,
>>> We usually have HF/6-311+G** for sugars with charges (both geometry
>>> optimization and ESP calculations).  I am not sure if this would be the
>>> problem.
>>> I have the same thoughts for where the problems might also be.  I
>>> usually don’t see ring distortion like that.  But, I did not derive
>>> charges for sialic acid.  I will ask around for people in our lab who
>>> have worked on this sugar to see if the ring distortion in it is common.
>>> Thank you!
>>> Best regards,
>>> Xiao
>>>
>>>
>>> Xiaocong Wang
>>> Complex Carbohydrate Research Center
>>> The University of Georgia
>>> 315 Riverbend Road,
>>> Athens, GA, 30602
>>> Tel: (706) 254-7958
>>> E-mail: [log in to unmask]
>>> ------------------------------
>>> *From:* Users of GLYCAM & GLYCAM-Web <[log in to unmask]> on
>>> behalf of Lee-Ping Wang <[log in to unmask]>
>>> *Sent:* Monday, July 23, 2018 11:24:15 PM
>>> *To:* [log in to unmask]
>>> *Subject:* Re: Comparing self-derived GLYCAM charge parameters
>>>
>>> Hello Xiaocong,
>>>
>>> Thanks for your reply!
>>>
>>> 1) We used HF/6-31G* for constrained energy minimization and also for
>>> the ESP calculations.
>>>
>>> 2) We set the charges on certain hydrogens in 0SA to zero, based on
>>> whether they were bonded to carbon. The atom names are: H3E, H3A, H4, H5,
>>> H6, H7, H8, H9S, H9R, H3M, H2M, H1M. I think these are the same hydrogens
>>> that got zero charges in GLYCAM. For OME we froze all of the charges and
>>> did not optimize them at all, which meant hydrogens H1, H2, H3 had charges
>>> of zero in the calculation.
>>>
>>> At the moment, the only “problem” I can imagine is that the constrained
>>> energy minimizations might be causing some unexpected large distortions of
>>> the sugar ring, because the ring dihedral angles are not being constrained
>>> (e.g. see the picture highlighting C3-C4-C5-C6 from the original email).  I
>>> am attaching a table of our ensemble-averaged charges and the standard
>>> deviations, and the standard deviations of carbon charges are rather large
>>> (σ = 0.05 ~ 0.13).
>>>
>>> Have you ever seen major distortions of the 6-membered ring in the
>>> constrained minimizations?  Do you think that constraining the ring
>>> dihedral angles is a good idea?
>>>
>>> Thanks,
>>>
>>> - Lee-Ping
>>>
>>>
>>>
>>> On Jul 23, 2018, at 6:57 PM, Xiaocong Wang <[log in to unmask]> wrote:
>>>
>>> Dear Dr. Wang,
>>> Your procedure is the same as what we did for deriving ensemble-averaged
>>> partial atomic charge sets for carbohydrate molecules.  It is a very
>>> thorough work for reproducing charge sets for 0SA.  I have two questions
>>> about calculation detail:  1. What level of theories did you use for
>>> geometry optimization and ESP calculation? 2. In step 6, by "aliphatic
>>> hydrogens", you mean all aliphatic hydrogen atoms in 0SA+OME, not just
>>> those in OME?
>>> The purpose of ensemble-averaged charge sets is to have better
>>> representations of electrostatic properties for exocyclic groups.  From my
>>> experience, charge values for ring carbon atoms are usually stable.  I am
>>> not sure what caused this variation, but I am happy to take a closer look
>>> if I can get more info.
>>> Best regards,
>>> Xiao
>>>
>>> Xiaocong Wang
>>> Complex Carbohydrate Research Center
>>> The University of Georgia
>>> 315 Riverbend Road,
>>> Athens, GA, 30602
>>> Tel: (706) 254-7958
>>> E-mail: [log in to unmask]
>>> ------------------------------
>>> *From:* Users of GLYCAM & GLYCAM-Web <[log in to unmask]> on
>>> behalf of Lee-Ping Wang <[log in to unmask]>
>>> *Sent:* Monday, July 23, 2018 6:29:17 PM
>>> *To:* [log in to unmask]
>>> *Subject:* Comparing self-derived GLYCAM charge parameters
>>>
>>> Hello there,
>>>
>>> We’re carrying out some studies on chemically modified sialic acids -
>>> specifically N-acetylation at the C4, C7, C8, or C9 positions.  Because
>>> there are many potential acetylation sites, we became interested in
>>> questions such as: (1) how much do the charges depend on the N-acetylation
>>> site, and (2) how much does the N-acetylation affect the charges on the
>>> sialic acid itself.
>>>
>>> For the initial step in our studies, we tried to reproduce your charge
>>> derivation for unmodified sialic acid (residue 0SA).  We obtained results
>>> that were quite close to the original GLYCAM charges, but there are still
>>> some differences and I’m not sure how significant they are.  *I’d like
>>> to know if we’re following your procedure correctly*, or if there’s
>>> anything we should be doing differently to improve the agreement.
>>>
>>> Here is the procedure we used:
>>>
>>> 1) Using tleap, we created the oligosaccharide sequence OME 0SA (using
>>> the GLYCAM_06j-1 force field).
>>> 2) The system was neutralized by adding one Na+ and solvated in a box of
>>> TIP3P water.
>>> 3) We ran 200 ns of unbiased MD simulation and saved 100 structures of
>>> the oligosaccharide equally spaced at 2 ns intervals.
>>> 4) We energy-minimized each structure at the HF/6-31G* level of theory
>>> with all exocyclic dihedral angles constrained to their values from the MD
>>> structure.  (Note: these calculations sometimes cause the ring dihedral
>>> angles to change significantly.  In one calculation, the C3-C4-C5-C6
>>> dihedral angle increased from -66 to +13 degrees; see picture.)
>>> 5) We generated grids and calculated ESP values for each minimized
>>> structure using Gaussian and the options "Pop=chelpg  IOp(6/33=2)”.
>>> 6) We ran RESP on each individual structure using the resp program from
>>> AmberTools.
>>> Charges on all atoms were restrained (including hydrogen) with a weight
>>> of 0.01.
>>> Charges on OME were held constant and charges on aliphatic hydrogens
>>> were set to zero.
>>> We preferred to use the old resp program rather than RED server because
>>> the former gave us a better understanding of the process.
>>> 7) The set of 100 RESP-optimized charges were averaged to obtain the
>>> final result.
>>> 8) The final charges are plotted vs. the GLYCAM charges for comparison
>>> (see picture).
>>>
>>> The largest charge difference was on C2: 0.237 (GLYCAM) vs. 0.069 (our
>>> charges), a difference of 0.168.
>>> For polar atoms (|q| > 0.5) the largest difference was on C1: 0.789
>>> (GLYCAM), vs. 0.874 (our charges), a difference of 0.087.
>>> Generally, the most significant differences were on the carbon atoms
>>> (+/- 0.04–0.10 for C3–C9).
>>>
>>> 9) We also repeated steps 3-8 with a 500 ns simulation, taking 100
>>> snapshots equally spaced at 5 ns intervals.  The results are very close to
>>> our 200 ns results, with the greatest charge difference being 0.013.  With
>>> a 1000 ns sampling simulation, the largest charge difference vs. 200 ns is
>>> 0.023.  Thus, I do not think our results depend much on the trajectory
>>> length.
>>>
>>> I’m very interested in your thoughts on these results.  Thanks again!
>>>
>>> Sincerely,
>>>
>>> Lee-Ping Wang
>>> Assistant Professor
>>> Department of Chemistry, UC Davis
>>>
>>> <Geometries.png>
>>>
>>> <Charges.png>
>>>
>>>
>>>
>>
>> --
>> :-) Lachele
>> Lachele Foley
>> CCRC/UGA
>> Athens, GA USA
>>
>
>

-- 
:-) Lachele
Lachele Foley
CCRC/UGA
Athens, GA USA