[gmx-users] frozen ligand for free energy calculations

[Justin Lemkul]

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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