[gmx-users] Checking the possibility of one complex out of possible two

[Justin Lemkul]

On 3/31/14, 10:29 PM, Pappu Kumar wrote:
> Decoupling seems only feasible for small ligands. I tried to decople a protein
> but the grompp does not converge. Could you tell me the maximum size of the
> molecule that is feasible for decoupling? I already calculated the free energy
> of solvation by APBS.
>

Decoupling only works efficiently for small molecules.  I don't know of a hard 
rule that defines what "small" is, but the more flexible the molecule is, the 
more difficult it becomes to deal with.  Theoretically, you can make anything 
work, but convergence can be hard to attain for anything that is too large.

-Justin

> Now I am pulling out one monomer from the other in both cases and checking the
> PMF along the trajectory using your tutorial on umbrella sampling. Thanks.
> On Monday, 31 March 2014 8:06 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>
>
> On 3/31/14, 6:07 AM, Pappu Kumar wrote:
>  > In the two protein dimers, the location of one monomer is at the opposite side
>  > of the other monomer :
>  >
>  > (| 0 and 0 |)
>  >
>  > when they are aligned (0 - common monomer, (| or |) the other monomer). So it
>  > would be hard to get the reaction coordinate for PMF calculation.
>  >
>  > I am wondering if I can compare the free energy of decoupling from water of two
>  > dimers separately by TI (g_bar). Can I use the same techinique in case of a
>  > point mutation? Thank you.
>  >
>
> Doubtful.  Decoupling a whole protein is impractical from both a performance and
> analysis standpoint.  The simulations will probably never reach convergence and
> will sample a bunch of really unphysical states.  Something like MM/PBSA would
> be much more sensible.
>
> -Justin
>
>  > On Friday, 28 March 2014 7:40 AM, Justin Lemkul <jalemkul at vt.edu
> <mailto:jalemkul at vt.edu>> wrote:
>  >
>  >
>  > On 3/27/14, 1:59 PM, Pappu Kumar wrote:
>  >  > I got two long protein complexes made out of 20 monomers of ~300 residues.
>  >  > But only one complex exists biologically. I am trying to find out the
>  >  > energetically favourable complex by MD simulation in gromacs 4.6.5. Initially
>  >  > I took out a dimer from the complexes and ran steepest descent followed by
>  >  > L-BFGS minimization . Although the total energy was lower in one dimer, after
>  >  > the L-BFGS, the energy was similar.
>  >  >
>  >  > Then I ran 50ns MD simulation and calculated the interaction energies between
>  >  > the monomers which is similar in both cases. The idea was that in the wrong
>  >  > confomation the interaction energy would be lower.
>  >  >
>  >  > Now I am wondering how to find out the correct conformation between the two
>  >  > possibilites. I also checked the free energy of solvation which is different
>  >  > in both cases. I am not sure if it is a clear indicator of stability since
>  >  > entropy is not taken into account. Let me know if you have any ideas. I am
>  >  > planning to run coarse grained simulations in MARTINI.  Thank you.
>  >
>  >  >
>  >
>  > Calculating an actual deltaG of binding (i.e. a PMF) between the two monomers is
>  > about the only legitimate way I can think of to do this.  The values of
>  > potential energy in a minimized structure are totally dependent on the force
>  > field, as are the nonbonded interaction energies, which (more importantly)
>  > aren't necessarily parametrized to be anything useful.
>  >
>  > -Justin
>  >
>  > --
>  > ==================================================
>  >
>  > Justin A. Lemkul, Ph.D.
>  > Ruth L. Kirschstein NRSA Postdoctoral Fellow
>  >
>  > Department of Pharmaceutical Sciences
>  > School of Pharmacy
>  > Health Sciences Facility II, Room 601
>  > University of Maryland, Baltimore
>  > 20 Penn St.
>  > Baltimore, MD 21201
>  >
>  > jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu>
> <mailto:jalemkul at outerbanks.umaryland.edu
> <mailto:jalemkul at outerbanks.umaryland.edu>> |
>  > (410) 706-7441
>  > http://mackerell.umaryland.edu/~jalemkul
>
>  >
>  >
>  > ==================================================
>  >
>  >
>
> --
> ==================================================
>
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 601
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
>
> jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu> |
> (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul
>
> ==================================================
>
>

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

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 601
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

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