OK, I am trying to reproduce the paper procedure.
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
> On 30 Nov 2015, at 10:57 AM, hannes.loeffler.stfc.ac.uk wrote:
>
> The restraints are just used for the preparation stage to avoid any sudden and potentially bad conformational changes before the final temperature has been reached. If you think this could be a problem for you ligand then use restraints too. I can't see how it would hurt. For production you would run without restraints of course.
>
> ________________________________________
> From: Fabian gmail [fabian.glaser.gmail.com <mailto:fabian.glaser.gmail.com>]
> Sent: 29 November 2015 16:08
> To: AMBER Mailing List
> Subject: Re: [AMBER] free energy of solvation of small molecules
>
> 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> <mailto: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 <http://bku.technion.ac.il/>
>>>
>>>
>>>> On 25 Nov 2015, at 3:03 PM, <hannes.loeffler.stfc.ac.uk <mailto:hannes.loeffler.stfc.ac.uk>>
>>>> <hannes.loeffler.stfc.ac.uk <mailto: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 <mailto: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>>><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/> <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> <mailto: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> <mailto: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/> <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> <mailto: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> <mailto: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?
>>>>>>>
>>>>>>> _______________________________________________
>>>>>>> AMBER mailing list
>>>>>>> AMBER.ambermd.org <mailto:AMBER.ambermd.org>
>>>>>>> http://lists.ambermd.org/mailman/listinfo/amber <http://lists.ambermd.org/mailman/listinfo/amber>
>>>>>>
>>>>>> _______________________________________________
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>>>>>
>>>>>
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Received on Mon Nov 30 2015 - 01:30:03 PST
