[gmx-users] frozen ligand for free energy calculations

[Ahmet Yildirim]

OK, thanks. Which of the following option do you suggest me under
intermolecular interactions?
1) function type 6, 1 and 1 for [ bonds ], [ angles ] and [ dihedrals ]
respectively
2) function type 6, 1 and 1 for [ bonds ], [ angle_restraints ] and[
dihedral_restraints ] respectively
3) function type 10, 1 and 1 for [ distance_restraints ], [
angle_restraints ] and [ dihedral_restraints ] respectively



On 13 July 2017 at 17:21, Justin Lemkul <jalemkul at vt.edu> wrote:

>
>
> On 7/13/17 9:59 AM, Ahmet Yildirim wrote:
>
>> Dear users,
>>
>> I come across with an issue when I try to do free energy calculations. The
>> issue is about the roto-translational motions of the ligand in the
>> decoupled state. I mean the ligand doesn't stay stable in the binding
>> pocket as in the coupled state.
>> It seems that the restraints that are applied on the atoms of the protein
>> and ligand under [ intermolecular_interactions ] part (an example of it is
>> below) in the compex top file aren't sufficient to keep the ligand from
>> repositioning/rotation with respect to the protein in the decoupled state.
>> Even one, two and three sets of restraints couldn't solve the issue.
>>
>> [ intermolecular_interactions ]
>> [ bonds ]
>> ; ai      aj    type   bA           kA       bB        kB
>>    629     3     6      0.597        0.0      0.597     4184.0
>>
>> [ angles ]
>> ; ai      aj    ak    type   thA          fcA      thB        fcB
>>    281   629     3     1       37.5        0.0       37.5      41.84
>>    629     3    21     1      121.5        0.0      121.5      41.84
>>
>> [ dihedrals ]
>> ; ai     aj     ak    al    type    thA         fcA       thB       fcB
>>    249   281   629     3     2     -147.4        0.0     -147.4      41.84
>>    281   629     3    21     2      -60.5        0.0      -60.5      41.84
>>    629     3    21    16     2     -153.9        0.0     -153.9      41.84
>>
>>
> Here, with function type 2, you're specifying improper dihedrals.  This
> isn't going to be what you want.  You probably want to be using a series of
> dihedral restraints, not actual dihedrals.
>
> <snip>
>
> I would try to freeze the ligand in the decoupled state in the canonical
>> ensemle with the above restrains under [ intermolecular_interactions ] but
>> I am not sure whether that makes sense or not? Justin says (
>> https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users
>> /2013-August/083647.html):
>>
>> "...Anything that is frozen, by definition, never has its position
>> updated.  Under the influence of
>> pressure coupling, other particles around the frozen group can have their
>> positions scaled and thus collide with the frozen group, which has
>> remained
>> in
>> its original location". I think I can use the frozen ligand in both
>> coupled
>> and decoupled state? And I should take into consideration the effect of
>> the
>> frozen ligand on the free energy calculation, right?
>>
>>
> By doing this, you're negating any conformational sampling of the ligand,
> therefore its entropy is wrong, and if the protein drifts and the ligand
> stays put (because it's frozen) that's a fairly useless state.  The
> appropriate strategy is a system of intermolecular interactions, but they
> need to be properly defined.  As well, the choice of atoms can be
> significant, e.g. dx.doi.org/10.1021/ci300505n and references therein.
>
> -Justin
>
> --
> ==================================================
>
> 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 Yildirim