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?
Thanks a lot,
Fabian
charge method abbre. index | charge method abbre. index
----------------------------------------------------------------
RESP resp 1 | AM1-BCC bcc 2
CM1 cm1 3 | CM2 cm2 4
ESP (Kollman) esp 5 | Mulliken mul 6
Gasteiger gas 7 | Read in charge rc 8
Write out charge wc 9 | Delete Charge dc 10
----------------------------------------------------------------
.<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
1 1 2 ar
2 1 7 ar
3 1 24 1
4 2 3 ar
5 2 23 1
6 3 4 ar
7 3 5 1
8 4 6 ar
9 4 22 1
10 5 8 2
11 5 9 2
12 5 10 1
13 6 7 ar
14 6 11 1
15 7 13 1
16 10 25 1
17 10 26 1
18 11 14 1
19 11 19 1
20 11 20 1
21 12 13 1
22 12 14 1
23 12 17 1
24 12 18 1
25 13 15 1
26 13 16 1
27 14 21 1
.<TRIPOS>SUBSTRUCTURE
1 SKF 1 TEMP 0 **** **** 0 ROOT
/Users/admin/Data/TUTORIALS/AMBER/A9/1HNN
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 19 Nov 2015, at 6:54 PM, Hannes Loeffler <Hannes.Loeffler.stfc.ac.uk> wrote:
>
> Dear Fabian,
>
> what you could try is "absolute" free energy simulation where you
> completely "destroy" the ligand. This means you mutate it into nothing
> and does get the solvation free energy. Have a look
> into http://pubs.acs.org/doi/abs/10.1021/ct400340s <http://pubs.acs.org/doi/abs/10.1021/ct400340s> how to do that. The
> SI of that paper describes how to prepare inputs with sample scripts.
>
> Your ligands are very dissimilar anyway so computing relative free
> energies by mutating them into each other may be problematic and
> difficult to do. But you ligands are also very large so you should
> carefully monitor if your free energy converges and also look into the
> statistics.
>
> Cheers,
> Hannes.
>
>
> On Thu, 19 Nov 2015 18:40:19 +0200
> Fabian gmail <fabian.glaser.gmail.com <mailto:fabian.glaser.gmail.com>> wrote:
>
>> Dear Hannes,
>>
>> Sorry to bother you, I went through the A9 tutorial in detail, and I
>> have several additional questions to my specific goals and molecules:
>>
>> I am not sure how to construct my thermodynamic cycle, in my case
>> there is no protein, only two different ligands, for what I saw in
>> your tutorial cycle, you need a protein medium to run MD and mutate
>> the ligand. In my case the protein medium does not exist and the
>> ligands are very big and quite different… I would prefer not to
>> mutate them if possible.
>>
>> Another possibility for me would be to run two different type of
>> solvents, one would be the ligand in pure water and the other in
>> water + acetone for example and calculate the difference between the
>> two ligands. And then I would calculate the DG of transfer between
>> water to water + acetone or the hydration in water + acetone, which
>> is very close to what really happens, Is this doable with TI?
>>
>> Additionally, the ligands I consider are very very flexible large and
>> different see them:
>>
>> https://en.wikipedia.org/wiki/Darunavir
>> <https://en.wikipedia.org/wiki/Darunavir <https://en.wikipedia.org/wiki/Darunavir>>
>> https://en.wikipedia.org/wiki/Ritonavir <https://en.wikipedia.org/wiki/Ritonavir>
>> <https://en.wikipedia.org/wiki/Ritonavir>
>>
>> Can they be mutated into each other without accumulating charge
>> errors?
>>
>> I think I would prefer not to mutate them but to calculate the
>> hydration free energies of each of them in water and / or in water +
>> acetone mixtures.
>>
>> Is that a good approach?
>>
>> Thansk a lot again,
>>
>> 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 17 Nov 2015, at 6:06 PM, Hannes Loeffler
>>> <Hannes.Loeffler.stfc.ac.uk> wrote:
>>>
>>> On Tue, 17 Nov 2015 17:35:04 +0200
>>> Fabian gmail <fabian.glaser.gmail.com> wrote:
>>>
>>>> Dear Hannes,
>>>>
>>>> Thanks a lot, it looks very interesting and relevant, my molecules
>>>> are much larger (ritonavir and darunavir) but still I maybe able to
>>>> use similar ideas.
>>>
>>> Regarding the number of atoms the following may be of use
>>> https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users/2015-July/099194.html
>>>
>>> _______________________________________________
>>> AMBER mailing list
>>> AMBER.ambermd.org
>>> http://lists.ambermd.org/mailman/listinfo/amber
>>
>> _______________________________________________
>> AMBER mailing list
>> AMBER.ambermd.org <mailto:AMBER.ambermd.org>
>> http://lists.ambermd.org/mailman/listinfo/amber <http://lists.ambermd.org/mailman/listinfo/amber>
>
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org <mailto:AMBER.ambermd.org>
> http://lists.ambermd.org/mailman/listinfo/amber <http://lists.ambermd.org/mailman/listinfo/amber>
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Wed Nov 25 2015 - 02:00:04 PST
