[gmx-users] pretty large coulomb contribution to free energy

[Ahmet Yıldırım]

To test that patched GROMACS version there is not any information about how
[ intermolecular-interactions ] must add to .top file in manual/your
tutorials. Maybe you can paste here an example .top file you have recently
used with that version :)  Is that possible?

2015-06-27 1:56 GMT+02:00 Justin Lemkul <jalemkul at vt.edu>:

>
>
> On 6/26/15 4:44 PM, Ahmet Yıldırım wrote:
>
>> Dear users,
>>
>> The free energy of decoupling the ligand from the complex I get is about
>> 457 kcal/mol. If for ligand in solution I get -5 kcal/mol, and for the
>> restraints -8 kcal/mol. Binding free energy is 457-5-8=444 kcal/mol. A
>> value over 400-500 kcal/mol is not unexpected for decoupling the ligand
>> from the complex? Anyone experienced similar problem? The problem is the
>> intramolecular interaction of the ligand? How about this Gromacs version
>>
>> https://github.com/gromacs/gromacs/tree/022ad08b2fd0c1de085e88ac81a61841c4daea9c
>> ?
>>
>>
> For proper absolute binding free energies, you need these restraints.  I'm
> actually using that patched version now and it's essential for getting
> reasonable energies in protein-ligand complexes.  Otherwise you sample a
> ton of totally nonphysical configurations in (nearly) decoupled states.
> Even just the pull code is not enough; that provides a translational
> restraint, but the orientation can vary.  See, e.g.
> dx.doi.org/10.1021/ci300505n for a very robust method that can easily be
> done in GROMACS now using the intermolecular bondeds.
>
> -Justin
>
>
>  Ligand I used is neutral. Gromacs version is 4.6.5
>>
>> Free energy control parts of my input files are below.
>>
>> ############ For decoupling the ligand from the complex #########
>> ; Free energy control stuff
>> init-lambda-state        = 5
>> free_energy              = yes
>> sc-alpha                 = 0.5
>> sc-power                 = 1.0
>> sc-sigma                 = 0.3
>> restraint-lambdas        = 0.0 0.01 0.025 0.05 0.075 0.1 0.2 0.35 0.5 0.75
>> 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.00 1.0 1.0 1.0 1.0 1.0 1.0
>> 1.00 1.0 1.00 1.0 1.00 1.0 1.00 1.0
>> coul-lambdas             = 0.0 0.00 0.000 0.00 0.000 0.0 0.0 0.00 0.0 0.00
>> 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.00 1.0 1.0 1.0 1.0 1.0 1.0
>> 1.00 1.0 1.00 1.0 1.00 1.0 1.00 1.0
>> vdw-lambdas              = 0.0 0.00 0.000 0.00 0.000 0.0 0.0 0.00 0.0 0.00
>> 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.05 0.1 0.2 0.3 0.4 0.5 0.6
>> 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1.0
>> nstdhdl                  = 10
>>
>> pull           = umbrella
>> pull_geometry  = distance
>> pull_dim       = Y Y Y
>> pull_start     = no
>> pull_init1     = 0.2980769
>>
>> pull_ngroups   = 1
>> pull_group0    = atom-p
>> pull_group1    = atom-l
>> pull_k1        = 0.0   ; kJ*mol^(-1)*nm^(-2)
>> pull_kB1       = 4184  ; kJ*mol^(-1)*nm^(-2)
>>
>>
>> ######## For solvation free energy ###########
>> ; Free energy control stuff
>> init-lambda-state        = 5
>> free_energy              = yes
>> sc-alpha                 = 0.5
>> sc-power                 = 1.0
>> sc-sigma                 = 0.3
>> coul-lambdas             = 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
>> 1.00
>> 1.0 1.0 1.0 1.0 1.0 1.0 1.00 1.0 1.00 1.0 1.00 1.0 1.00 1.0
>> vdw-lambdas              = 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
>> 0.05
>> 0.1 0.2 0.3 0.4 0.5 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1.0
>> nstdhdl                  = 10
>> couple-intramol          = yes
>> couple-moltype           = MOL
>> couple-lambda0           = vdw-q
>> couple-lambda1           = none
>>
>>
>>
>>
> --
> ==================================================
>
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 629
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
>
> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul
>
> ==================================================
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-- 
Ahmet Yıldırım