Hi,

No, I have not tried it for a simpler molecule. I thought initially to do
something like ethane to ethanol which would be appropriate I guess. But
decide to mail to the forum to know if I was missing something obvious. The
protocol is based on my understanding of a few papers from Mobley group and
uses the setup scripts provided by them.

But as you also suggest, I should try this for a simpler system and see if
it works.

Thank you Mark.





On Sat 11 Aug, 2018, 05:02 Mark Abraham, <mark.j.abra...@gmail.com> wrote:

> Hi,
>
> Sorry for not having time to dig in detail, but does your protocol work for
> a simpler molecule?
>
> Mark
>
> On Fri, Aug 10, 2018, 13:33 Abhishek Acharya <abhi117acha...@gmail.com>
> wrote:
>
> > Dear Gromacs Users,
> >
> > I am trying to calculate the relative hydration free energy of Catechol
> wrt
> > Benzene as a way of validating the parameters of Catechol, which I need
> for
> > further free energy calculations. I am using OPLS-AA for these
> calculations
> > and the parameters for both Catechol and Benzene were generated using the
> > LigParGen webserver. Subsequently, I used the alchemical_setup.py script
> (
> > https://github.com/MobleyLab/alchemical-setup) to generate the topology
> > for
> > transformation of catechol to benzene. This was followed by the necessary
> > steps to generate a solvated system.
> >
> > Relative hydration free energy was calculated in 3 steps:
> >
> > a) Discharging catechol using the following topology setup done (using 11
> > lambda values):
> >
> > ;   nr       type  resnr    res   atom   cgnr     charge       mass
> > typeB    chargeB      massB comments  MCSS = Minimum Common Sub-Structure
> >      1   opls_800      1    LIG     C1      1    -0.1361    12.0110
> > opls_800     0.0    12.0110 ; MCSS
> >      2   opls_801      1    LIG     C2      2    -0.1361    12.0110
> > opls_801     0.0    12.0110 ; MCSS
> >      3   opls_802      1    LIG     C3      3    -0.1693    12.0110
> > opls_802     0.0    12.0110 ; MCSS
> >      4   opls_803      1    LIG     C4      4     0.2517    12.0110
> > opls_803     0.0    12.0110 ; MCSS
> >      5   opls_804      1    LIG     C5      5     0.3382    12.0110
> > opls_804     0.0    12.0110 ; MCSS
> >      6   opls_805      1    LIG     C6      6    -0.1693    12.0110
> > opls_805     0.0    12.0110 ; MCSS
> >      7   opls_810      1    LIG    HA1      7     0.1508     1.0080
> > opls_808     0.0     1.0080 ; MCSS
> >      8 opls_810_dummy      1    LIG    HA2      8    0.00000     1.0080
> > opls_810     0.0     1.0080 ; to be appeared
> >      9   opls_811      1    LIG    HB1      9     0.1508     1.0080
> > opls_811     0.0     1.0080 ; MCSS
> >     10   opls_812      1    LIG    HC1     10     0.4461     1.0080
> > opls_812_dummy    0.00000     1.0080 ; to be annihilated
> >     11   opls_813      1    LIG    HD1     11     0.4422     1.0080
> > opls_813_dummy    0.00000     1.0080 ; to be annihilated
> >     12   opls_806      1    LIG     O1     12    -0.7156    15.9990
> > opls_806_dummy    0.00000    15.9990 ; to be annihilated
> >     13   opls_807      1    LIG     O2     13     -0.742    15.9990
> > opls_807_dummy    0.00000    15.9990 ; to be annihilated
> >     14   opls_808      1    LIG     H1     14     0.1443     1.0080
> > opls_808     0.0     1.0080 ; MCSS
> >     15   opls_809      1    LIG     H2     15     0.1443     1.0080
> > opls_809     0.0     1.0080 ; MCSS
> >     16 opls_809_dummy      1    LIG     H3     16    0.00000     1.0080
> > opls_809     0.0     1.0080 ; to be appeared
> >
> > Here only coulomb-lambdas were varied as: 0.00 0.10 0.20 0.30 0.40 0.50
> > 0.60 0.70 0.80 0.90 1.00
> >
> > b) LJ-transformation from catechol to benzene (26 lambda values):
> >
> > ;   nr       type  resnr    res   atom   cgnr     charge       mass
> > typeB    chargeB      massB comments  MCSS = Minimum Common Sub-Structure
> >      1   opls_800      1    LIG     C1      1     0.0    12.0110
> > opls_800     0.0    12.0110 ; MCSS
> >      2   opls_801      1    LIG     C2      2     0.0    12.0110
> > opls_801     0.0    12.0110 ; MCSS
> >      3   opls_802      1    LIG     C3      3     0.0    12.0110
> > opls_802     0.0    12.0110 ; MCSS
> >      4   opls_803      1    LIG     C4      4     0.0    12.0110
> > opls_803     0.0    12.0110 ; MCSS
> >      5   opls_804      1    LIG     C5      5     0.0    12.0110
> > opls_804     0.0    12.0110 ; MCSS
> >      6   opls_805      1    LIG     C6      6     0.0    12.0110
> > opls_805     0.0    12.0110 ; MCSS
> >      7   opls_808      1    LIG    HA1      7     0.0     1.0080
> > opls_808     0.0     1.0080 ; MCSS
> >      8 opls_810_dummy      1    LIG    HA2      8    0.0     1.0080
> > opls_810     0.0     1.0080 ; to be appeared
> >      9   opls_811      1    LIG    HB1      9     0.0     1.0080
> > opls_811     0.0     1.0080 ; MCSS
> >     10   opls_812      1    LIG    HC1     10     0.0     1.0080
> > opls_812_dummy    0.0     1.0080 ; to be annihilated
> >     11   opls_813      1    LIG    HD1     11     0.0     1.0080
> > opls_813_dummy    0.0     1.0080 ; to be annihilated
> >     12   opls_806      1    LIG     O1     12     0.0    15.9990
> > opls_806_dummy    0.0    15.9990 ; to be annihilated
> >     13   opls_807      1    LIG     O2     13     0.0    15.9990
> > opls_807_dummy    0.0    15.9990 ; to be annihilated
> >     14   opls_808      1    LIG     H1     14     0.0     1.0080
> > opls_808     0.0     1.0080 ; MCSS
> >     15   opls_809      1    LIG     H2     15     0.0     1.0080
> > opls_809     0.0     1.0080 ; MCSS
> >     16 opls_809_dummy      1    LIG     H3     16    0.0     1.0080
> > opls_809     0.0     1.0080 ; to be appeared
> >
> > Here only vdw-lambdas were varied as:
> > vdw_lambdas               = 0.00 0.04 0.08 0.12 0.16 0.20 0.24 0.28 0.32
> > 0.36 0.40 0.44 0.48 0.52 0.56 0.60 0.64 0.68 0.72 0.76 0.80 0.84 0.88
> 0.92
> > 0.96 1.00
> >
> > Meanwhile, coulomb_lambdas were kept 0 throughout, as the charges of
> State
> > A and B have been set to zero in this topology.
> >
> > c) Recharging to full benzene charges (11 lambda values):
> >
> > ;   nr       type  resnr    res   atom   cgnr     charge       mass
> > typeB    chargeB      massB comments  MCSS = Minimum Common Sub-Structure
> >      1   opls_800      1    LIG     C1      1     0.0    12.0110
> > opls_800    -0.1474    12.0110 ; MCSS
> >      2   opls_801      1    LIG     C2      2     0.0    12.0110
> > opls_801    -0.1476    12.0110 ; MCSS
> >      3   opls_802      1    LIG     C3      3     0.0    12.0110
> > opls_802    -0.1474    12.0110 ; MCSS
> >      4   opls_803      1    LIG     C4      4     0.0    12.0110
> > opls_803    -0.1472    12.0110 ; MCSS
> >      5   opls_804      1    LIG     C5      5     0.0    12.0110
> > opls_804    -0.1470    12.0110 ; MCSS
> >      6   opls_805      1    LIG     C6      6     0.0    12.0110
> > opls_805    -0.1470    12.0110 ; MCSS
> >      7   opls_808      1    LIG    HA1      7     0.0     1.0080
> > opls_808     0.1474     1.0080 ; MCSS
> >      8   opls_810      1    LIG    HA2      8     0.0     1.0080
> > opls_810     0.1470     1.0080 ; to be appeared
> >      9   opls_811      1    LIG    HB1      9     0.0     1.0080
> > opls_811     0.1470     1.0080 ; MCSS
> >     10 opls_812_dummy      1    LIG    HC1     10     0.0     1.0080
> > opls_812_dummy    0.0     1.0080 ; to be annihilated
> >     11 opls_813_dummy      1    LIG    HD1     11     0.0     1.0080
> > opls_813_dummy    0.0     1.0080 ; to be annihilated
> >     12 opls_806_dummy      1    LIG     O1     12     0.0    15.9990
> > opls_806_dummy    0.0    15.9990 ; to be annihilated
> >     13 opls_807_dummy      1    LIG     O2     13     0.0    15.9990
> > opls_807_dummy    0.0    15.9990 ; to be annihilated
> >     14   opls_806      1    LIG     H1     14     0.0     1.0080
> > opls_806     0.1474     1.0080 ; MCSS
> >     15   opls_807      1    LIG     H2     15     0.0     1.0080
> > opls_807     0.1474     1.0080 ; MCSS
> >     16   opls_809      1    LIG     H3     16     0.0     1.0080
> > opls_809     0.1474     1.0080 ; to be appeared
> >
> > In this case the topology was changed a bit to have the same LJ
> parameters
> > for both State A and B = Benzene.
> > Lambda values used for this transformation were:
> > coul_lambdas              = 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80
> > 0.90 1.00
> > vdw_lambdas               = 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
> > 1.00 1.00 (Although, even a value of 0 throughout should work here)
> >
> > Finally, the free energy change for the these transformations were
> > calculated using the alchemical_analysis script (
> > https://github.com/MobleyLab/alchemical-analysis).
> > Result for the three steps [MBAR output only (in kcal/mol); statistical
> > error in brackets]: Discharging: 27.449 (0.028), LJ-transform: - 0.192
> > (0.001) and Recharging: - 0.348 (0.039)
> >
> > The problem is the the reported experimental value for relative hydration
> > free energy of catechol and benzene is around 8.5 kcal/mol which is very
> > different from the calculated value (27.6 kcal/mol). The simulations have
> > been performed using a similar (cutoff, electrostatics etc.) setup as
> > mentioned in the LigParGen paper. The default soft-core parameters were
> > used for all three steps.
> >
> > I also tried a one-step transformation (both vdw and coulomb lambda
> varied
> > simultaneously) and got a value of around 29 kcal/mol.
> >
> > Since, I am attempting a transmutation of this sort for the first time, I
> > wanted to be sure the setup is correct before I contact LigParGen
> authors.
> > Since this seems like a simple transformation, I expected differences
> > (between experimental and calculated values) of the order of 1.5-2
> kcal/mol
> > as seen in case of hydration free energies of test cases used in the
> > LigParGen paper. It would be nice to get some pointers as to what might
> be
> > going wrong with my setup.
> >
> > Thanks in advance.
> >
> > Abhishek Acharya
> > --
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