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

[Justin Lemkul]

On 6/26/15 9:17 PM, Ahmet Yıldırım wrote:
> 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?
>

The directive structure is no different from any other bonded directive.  After 
[molecules], insert the [intermolecular_interactions] directive, after which you 
insert any bonded directive ([angles], [dihedral_restraints], etc) with *global* 
atom numbers (which you can do because [molecules] have already been defined so 
the data structures with global numbering have been populated).  Likely you will 
have to fill in parameters because you'll be connecting non-standard things that 
don't correspond to conventional geometries.

-Justin

> 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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>

-- 
==================================================

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

==================================================