[gmx-users] Free energy calculation problem with too high dG

[Vlad]

I tried to do the decoupling and strangely the result is not the same
Below is the end of the log
The total dG is significantly less then previous and the last dG value is particularly small
I think total dG will get less with more precise lambda sampling (by 0.05 instead of 0.1)
The thing which still is strange is the value of entropy for the last lambda (in the previous case it was so high as well for the first lambda)

So you suggest to use restraints
Througout the simulation or also gradually switched off?

Thank you for help

Sincerely yours,
Vlad

Temperature: 300 K
Detailed results in kT (see help for explanation):
lam_A lam_B DG +/- s_A +/- s_B +/- stdev +/- 
0 1 0.66 0.02 0.03 0.00 0.03 0.00 0.21 0.00
1 2 0.62 0.01 0.01 0.01 0.01 0.01 0.21 0.00
2 3 2.15 0.04 0.29 0.04 0.29 0.04 0.79 0.01
3 4 0.82 0.01 0.11 0.02 0.11 0.02 0.38 0.00
4 5 0.69 0.01 0.02 0.01 0.02 0.01 0.35 0.01
5 6 0.58 0.01 0.09 0.01 0.09 0.01 0.35 0.01
6 7 0.42 0.01 0.08 0.01 0.08 0.01 0.34 0.01
7 8 0.28 0.01 0.06 0.01 0.06 0.01 0.33 0.01
8 9 0.20 0.01 0.02 0.02 0.02 0.01 0.31 0.00
9 10 0.13 0.03 0.05 0.02 0.05 0.02 0.32 0.01
10 11 4.19 0.02 0.06 0.02 0.06 0.02 0.22 0.01
11 12 4.13 0.04 0.00 0.01 0.00 0.01 0.21 0.01
12 13 8.13 0.05 0.14 0.05 0.14 0.05 0.46 0.01
13 14 7.87 0.02 0.11 0.03 0.12 0.03 0.49 0.02
14 15 7.67 0.03 0.09 0.03 0.10 0.03 0.51 0.02
15 16 7.38 0.04 0.19 0.05 0.20 0.05 0.57 0.03
16 17 7.09 0.09 0.08 0.06 0.10 0.06 0.62 0.01
17 18 6.67 0.08 0.33 0.06 0.36 0.06 0.75 0.03
18 19 5.95 0.04 0.36 0.04 0.46 0.05 0.90 0.03
19 20 4.62 0.05 0.87 0.11 1.39 0.16 1.51 0.06
20 21 0.49 0.07 1.12 0.07 1.73 0.12 1.68 0.05
21 22 -12.20 0.38 10.97 0.34 530033806446307904.00 343034015797650752.00 49.55 3.92

Final results in kJ/mol:
point 0 - 1, DG 1.63 +/- 0.06
point 1 - 2, DG 1.54 +/- 0.04
point 2 - 3, DG 5.37 +/- 0.10
point 3 - 4, DG 2.04 +/- 0.03
point 4 - 5, DG 1.71 +/- 0.03
point 5 - 6, DG 1.45 +/- 0.03
point 6 - 7, DG 1.04 +/- 0.03
point 7 - 8, DG 0.69 +/- 0.02
point 8 - 9, DG 0.50 +/- 0.03
point 9 - 10, DG 0.33 +/- 0.07
point 10 - 11, DG 10.44 +/- 0.04
point 11 - 12, DG 10.30 +/- 0.09
point 12 - 13, DG 20.27 +/- 0.12
point 13 - 14, DG 19.64 +/- 0.04
point 14 - 15, DG 19.13 +/- 0.07
point 15 - 16, DG 18.40 +/- 0.10
point 16 - 17, DG 17.70 +/- 0.22
point 17 - 18, DG 16.64 +/- 0.20
point 18 - 19, DG 14.85 +/- 0.10
point 19 - 20, DG 11.53 +/- 0.12
point 20 - 21, DG 1.23 +/- 0.19
point 21 - 22, DG -30.43 +/- 0.94
total 0 - 22, DG 146.01 +/- 0.95
 


>Вторник,  4 октября 2016, 15:15 +03:00 от Hannes Loeffler <Hannes.Loeffler at stfc.ac.uk>:
>
>On Tue, 4 Oct 2016 14:01:52 +0300
>Vlad < vlad_balaev at mail.ru > wrote:
>> No reason. I just thought it would give the same result. 
>
>In theory both directions should be symmetrical and give the same
>result.
>
>
>> In the trajectory the ligand diffuse to the end of the cell like a
>> ghost through the water molecules. And could the reason lie in the
>> fact that in the initial structure during all preparations the ligand
>> is "fully existing" and in the first step of simulation suddenly is
>> turned off? 
>
>
>I would suggest to have a look through
>http://www.alchemistry.org/wiki/Example:_Absolute_Binding_Affinity and
>other material on that web page.  In particular reference 1 on that
>page should be of interest to you in how to use restraints within a
>general scheme.
>
>In a homogeneous environment like water it doesn't matter that your
>"ghost" molecule drifts because on average the interactions with its
>environment will be the same regardless of location.  In an
>inhomogeneous environment, however, the nearly non-interacting ligand
>will have different probabilities of where it is located.  In
>principle, you would have to sample _all_ possible locations which in
>practice is hard or impossible.  Hence the restraint scheme as
>suggested above.
>
>Your ligand should exists as a bonded network throughout the
>simulation.  What you are doing however is "decoupling" which means
>that the non-bonded interactions between the ligand and its environment
>and vice versa a gradually switched off.
>
>
>Cheers,
>Hannes.
>-- 
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