[gmx-users] frozen ligand for free energy calculations
ahmedo047 at gmail.com
Thu Jul 13 17:51:15 CEST 2017
OK, thanks. Which of the following option do you suggest me under
1) function type 6, 1 and 1 for [ bonds ], [ angles ] and [ dihedrals ]
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.
> 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 (
>> "...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
>> its original location". I think I can use the frozen ligand in both
>> and decoupled state? And I should take into consideration the effect of
>> 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 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
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