Dear Hannes,
One more thing, I noticed in the tutorial A9 they use strong restraints during equilibration and heating, while in the Kaus paper they don’t use restraints at all.
Should I use restraints in my very flexible molecule to calculate the solvation free energy?
Or just allowing free MD will be better?
Thanks a lot,
Dr. Fabian Glaser
Head of the Structural Bioinformatics section
Bioinformatics Knowledge Unit - BKU
The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering
Technion - Israel Institute of Technology, Haifa 32000, ISRAEL
fglaser at technion dot ac dot il
Tel: +972 4 8293701
http://bku.technion.ac.il
> On 25 Nov 2015, at 5:38 PM, Hannes Loeffler <Hannes.Loeffler.stfc.ac.uk> wrote:
>
> The structure in the paper is protonated at the nitrogen which means
> that the total charge is +1.
>
> In Avogadro you should have a pencil icon in one of the top toolbars,
> otherwise Settings->Toolbars->Tools. When you click on it you should
> see a selection of elements in the left. Choose hyrogen, click your N
> while dragging away the new hydrogen. Extensions->Optimise Geometry if
> you wish.
>
> Cheers,
> Hannes.
>
>
> On Wed, 25 Nov 2015 17:15:06 +0200
> Fabian gmail <fabian.glaser.gmail.com <mailto:fabian.glaser.gmail.com>> wrote:
>
>> Thanks again,
>>
>> Yes I know all this, but I didn’t know a nitrogen can have a
>> tetrahedral symmetry without being charged…. (this molecule is zero
>> charged correct?). I downloaded installed and are able to see the
>> molecule with avogadro, looks great.
>>
>> Could you be so kind to explain me how to add a second hydrogen to
>> the N1 from the paper….?
>>
>> It is just to reproduce the tutorial, and then I will do the
>> calculations on my molecules.
>>
>> Thanks!!
>>
>>
>> Dr. Fabian Glaser
>> Head of the Structural Bioinformatics section
>>
>> Bioinformatics Knowledge Unit - BKU
>> The Lorry I. Lokey Interdisciplinary Center for Life Sciences and
>> Engineering Technion - Israel Institute of Technology, Haifa 32000,
>> ISRAEL
>>
>> fglaser at technion dot ac dot il
>> Tel: +972 4 8293701
>> http://bku.technion.ac.il
>>
>>
>>> On 25 Nov 2015, at 3:03 PM, <hannes.loeffler.stfc.ac.uk>
>>> <hannes.loeffler.stfc.ac.uk> wrote:
>>>
>>> I don't think this is weird at all.
>>>
>>> Crystal structures will most likely not have any hydrogens
>>> resolved. What I guess is happening is that some software will add
>>> hydrogens to fill the valencies. But protonation states, and more
>>> generally tautomeric states. are a function of the environment e.g.
>>> pH or the medium the molecule is embedded in. This is just basic
>>> chemistry. I would expect that particular nitrogen to be
>>> protonated in even moderately acidic aqueous solutions. In a
>>> protein environment, when that particular group binds for instance,
>>> the situation may be different again.
>>>
>>> Interactive graphical tools like chimera or avogadro (the ones I
>>> happen to know, but I'm sure there are many others) can be used to
>>> "draw" atddtional atoms.
>>>
>>> Cheers,
>>> Hannes.
>>>
>>> ________________________________________
>>> From: Fabian gmail [fabian.glaser.gmail.com
>>> <mailto:fabian.glaser.gmail.com <mailto:fabian.glaser.gmail.com>>] Sent: 25 November 2015 12:26
>>> To: AMBER Mailing List
>>> Subject: Re: [AMBER] free energy of solvation of small molecules
>>>
>>> Your are right!
>>>
>>> But the geometry of N1 is different on the drug bank….
>>>
>>> http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN <http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN>
>>> <http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN <http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN>><http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN <http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN>
>>> <http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN <http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId=SKF&sid=1HNN>>>
>>>
>>> Very weird, in any case could you please direct me how to change it?
>>>
>>> This cannot be a charged nitrogen…. the formal charge is zero.
>>>
>>> Very weird.
>>>
>>> thanks!!
>>>
>>> Fabian
>>>
>>>
>>>
>>>
>>> Dr. Fabian Glaser
>>> Head of the Structural Bioinformatics section
>>>
>>> Bioinformatics Knowledge Unit - BKU
>>> The Lorry I. Lokey Interdisciplinary Center for Life Sciences and
>>> Engineering Technion - Israel Institute of Technology, Haifa 32000,
>>> ISRAEL
>>>
>>> fglaser at technion dot ac dot il
>>> Tel: +972 4 8293701
>>> http://bku.technion.ac.il <http://bku.technion.ac.il/>
>>>
>>>
>>>> On 25 Nov 2015, at 1:10 PM, Hannes Loeffler
>>>> <Hannes.Loeffler.stfc.ac.uk <mailto:Hannes.Loeffler.stfc.ac.uk>> wrote:
>>>>
>>>> Your N1 is not protonated as it is in the paper.
>>>>
>>>> On Wed, 25 Nov 2015 12:39:59 +0200
>>>> Fabian gmail <fabian.glaser.gmail.com <mailto:fabian.glaser.gmail.com>> wrote:
>>>>
>>>>> Thanks for the detailed answer
>>>>>
>>>>> Well I tried several times to run reduce and antechamber with
>>>>> different options (e.g. with -Xplor parameter in reduce) but the
>>>>> names are not identical not in the PDB, but more importantly not
>>>>> in the mol2 file. And the charges are very different. The authors
>>>>> do use GAFF but with RESP for partial charges….
>>>>>
>>>>> "Partial charges for ligands were obtained using RESP38 fi tting
>>>>> for the electrostatic potentials calculated using Gaussian0339
>>>>> at the Hartree− Fock/6-31G* level of theory."
>>>>>
>>>>> As you can see the PDB indeed names the ligand correctly SKF, and
>>>>> so the sqm.pdb file, and indeed I used AM1-BCC charge method, but
>>>>> the charges and atoms types are indeed quite different, I paste
>>>>> both my results and their results for comparison…. I guess I will
>>>>> try anyway and see how different the results are.
>>>>>
>>>>> I guess the results will be different, but in any case I am
>>>>> looking for a certain degree of reproducibility before I start
>>>>> playing with my molecules, if the results are completely wrong
>>>>> well… I will rethink.
>>>>>
>>>>> THanks!!
>>>>>
>>>>> Fabian
>>>>>
>>>>>
>>>>> MY RESULTS
>>>>>
>>>>> .<TRIPOS>MOLECULE
>>>>> SKF
>>>>> 26 27 1 0 0
>>>>> SMALL
>>>>> bcc
>>>>>
>>>>>
>>>>> .<TRIPOS>ATOM
>>>>> 1 C4 28.3480 46.0370 16.7830 ca 3001 SKF
>>>>> -0.157000 2 C5 27.8990 45.5320 15.5700 ca 3001
>>>>> SKF -0.017000 3 C6 27.8220 44.1470 15.3850 ca
>>>>> 3001 SKF -0.387500 4 C7 28.1930 43.2860 16.4100
>>>>> ca 3001 SKF -0.010000 5 S 27.2610 43.4900
>>>>> 13.8470 sy 3001 SKF 1.528200 6 C8 28.6420
>>>>> 43.7900 17.6160 ca 3001 SKF -0.141300 7 C9
>>>>> 28.7200 45.1740 17.8070 ca 3001 SKF -0.008300 8
>>>>> O1 27.4850 44.4300 12.7700 o 3001 SKF
>>>>> -0.658800 9 O2 25.8660 43.1330 13.8730 o 3001 SKF
>>>>> -0.658800 10 N 28.1050 42.1870 13.5730 n3 3001
>>>>> SKF -1.026700 11 C1 28.9650 42.8430 18.7440 c3
>>>>> 3001 SKF 0.194100 12 C2 29.2110 44.8480 20.1940
>>>>> c3 3001 SKF 0.150800 13 C3 29.4880 45.7050
>>>>> 18.9780 c3 3001 SKF -0.087100 14 N1 29.7000
>>>>> 43.4830 19.8600 n3 3001 SKF -0.793200 15 HC32
>>>>> 30.4380 45.7060 18.7810 hc 3001 SKF 0.062700 16
>>>>> HC31 29.2340 46.6240 19.1540 hc 3001 SKF
>>>>> 0.062700 17 HC22 29.6670 45.1980 20.9750 h1 3001 SKF
>>>>> 0.059700 18 HC21 28.2630 44.8360 20.4000 h1 3001
>>>>> SKF 0.059700 19 HC12 28.1400 42.4640 19.0850 h1
>>>>> 3001 SKF 0.066200 20 HC11 29.4940 42.1070 18.3980
>>>>> h1 3001 SKF 0.066200 21 HN1 30.3490 43.1010
>>>>> 20.2760 hn 3001 SKF 0.353800 22 HC7 28.1370
>>>>> 42.3270 16.2790 ha 3001 SKF 0.153000 23 HC5
>>>>> 27.6400 46.1350 14.8560 ha 3001 SKF 0.152000 24
>>>>> HC4 28.4020 46.9960 16.9160 ha 3001 SKF
>>>>> 0.141000 25 H2N 27.9670 41.7280 12.8590 hn 3001 SKF
>>>>> 0.446800 26 H1N 28.7030 41.9350 14.1370 hn 3001
>>>>> SKF 0.446800 .<TRIPOS>BOND
>>>>>
>>>>>
>>>>> THEIR CHARGES AND ATOM TYPES
>>>>>
>>>>> Atom Name
>>>>> Atom Type
>>>>> Partial Charge
>>>>> O1
>>>>> S1
>>>>> O2
>>>>> N2
>>>>> H12
>>>>> H13
>>>>> C1
>>>>> C6
>>>>> H5
>>>>> C2
>>>>> H3
>>>>> C3
>>>>> H4
>>>>> C4
>>>>> C5
>>>>> C9
>>>>> H7
>>>>> H8
>>>>> N1
>>>>> H1
>>>>> H2
>>>>> C8
>>>>> H10
>>>>> H11
>>>>> C7
>>>>> H6
>>>>> H9
>>>>> o
>>>>> sy
>>>>> o
>>>>> n3
>>>>> hn
>>>>> hn
>>>>> ca
>>>>> ca
>>>>> ha
>>>>> ca
>>>>> ha
>>>>> ca
>>>>> ha
>>>>> ca
>>>>> ca
>>>>> c3
>>>>> hx
>>>>> hx
>>>>> n4
>>>>> hn
>>>>> hn
>>>>> c3
>>>>> hx
>>>>> hx
>>>>> c3
>>>>> hc
>>>>> hc
>>>>> -0.573668
>>>>> 1.232538
>>>>> -0.573668
>>>>> -1.037186
>>>>> 0.469850
>>>>> 0.469850
>>>>> -0.028732
>>>>> -0.216911
>>>>> 0.200250
>>>>> -0.129610
>>>>> 0.216974
>>>>> -0.225853
>>>>> 0.183828
>>>>> 0.053522
>>>>> 0.065648
>>>>> -0.178191
>>>>> 0.172836
>>>>> 0.172836
>>>>> -0.313324
>>>>> 0.348583
>>>>> 0.348583
>>>>> -0.090633
>>>>> 0.141132
>>>>> 0.141132
>>>>> 0.017190
>>>>> 0.066512
>>>>> 0.066512
>>>>>
>>>>>
>>>>>
>>>>> Dr. Fabian Glaser
>>>>> Head of the Structural Bioinformatics section
>>>>>
>>>>> Bioinformatics Knowledge Unit - BKU
>>>>> The Lorry I. Lokey Interdisciplinary Center for Life Sciences and
>>>>> Engineering Technion - Israel Institute of Technology, Haifa
>>>>> 32000, ISRAEL
>>>>>
>>>>> fglaser at technion dot ac dot il
>>>>> Tel: +972 4 8293701
>>>>> http://bku.technion.ac.il <http://bku.technion.ac.il/>
>>>>>
>>>>>
>>>>>> On 25 Nov 2015, at 12:16 PM, Hannes Loeffler
>>>>>> <Hannes.Loeffler.stfc.ac.uk <mailto:Hannes.Loeffler.stfc.ac.uk>> wrote:
>>>>>>
>>>>>> Dear Fabian.
>>>>>>
>>>>>> if the authors have used GAFF you should be able to obtain the
>>>>>> same atoms types. Charges will of course vary depending on the
>>>>>> derivation method you use. Principally free energies are
>>>>>> dependent on force field parameters but I won't be able to tell
>>>>>> you how much that would be (there are a few papers out there
>>>>>> which compare e.g. GAFF to OPLS).
>>>>>>
>>>>>> A few points to check:
>>>>>> Reduce reads a dictionary of known PDB structures so make sure
>>>>>> that your PDB file does indeed name the ligand as SKF. Check
>>>>>> reduce's output to make sure that is true. Make sure that the
>>>>>> hydrogens you have obtained are the same as in the paper. If so
>>>>>> you should get the same atom types.
>>>>>>
>>>>>> The charge models used for the AMBER family of force fields is
>>>>>> basically RESP or AM1/BCC (there are some exceptions but look
>>>>>> that up in the manual).
>>>>>>
>>>>>> Cheers,
>>>>>> Hannes
>>>>>>
>>>>>>
>>>>>> On Wed, 25 Nov 2015 11:43:36 +0200
>>>>>> Fabian gmail <fabian.glaser.gmail.com <mailto:fabian.glaser.gmail.com>> wrote:
>>>>>>
>>>>>>> Dear Hannes,
>>>>>>>
>>>>>>> I am trying to reproduce initially the results from the Kaus et
>>>>>>> al paper you mention for the first ligand
>>>>>>> ( 7-sulfamoyl-1,2,3,4-tetrahydroisoquinolinium), now if I am
>>>>>>> understand correctly first I need to obtain the mol2 file using
>>>>>>> antechamber with gaff model, starting from the PDB structure of
>>>>>>> this ligand this is what I tried to do using this commands:
>>>>>>>
>>>>>>> reduce SKF_A.pdb > SKF_hyd.pdb
>>>>>>> antechamber -i SKF_hyd.pdb -fi pdb -o SKF.mol2 -fo mol2 -c bcc
>>>>>>> -s 2
>>>>>>>
>>>>>>> This yields completely different atom types and charges as
>>>>>>> compared to the paper of Kaus, as expected since they used RESP
>>>>>>> model and I used AMB1-BCC, but I don’t have gaussian….
>>>>>>>
>>>>>>> Do you think the final DG value will be highly different using
>>>>>>> the bcc model or could you recommend to use a different model
>>>>>>> of those included in amber that I could use, which will provide
>>>>>>> more similar charges to the ones on the paper?
>>>>>>>
>>>>>>> Will those values highly impact the final results?
>>>>>>
>>>>>> _______________________________________________
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>>>>
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Received on Sun Nov 29 2015 - 08:30:03 PST
