[gmx-users] Binding energy of membrane protein to the membrane lipids

Thu May 8 21:39:27 CEST 2014

Dear all,

I'm trying to determine the binding energy of a membrane protein to the
membrane. Ultimately I need to compare the binding energy of the same
protein to two similar types of lipid, the hypothesis being that there
should be a slight difference.

I considered two options: alchemical transformations and umbrella sampling.
Alchemical transformations leave a very large vacuum in the membrane so are
nigh on impossible.

Justin Lemkul recommended I do this via pull/umbrella-sampling as he did in
his paper (http://dx.doi.org/10.1021/jp202217f). He was simulating a
single-helix protein, but one of the proteins I need to do this for is a
7-Transmembrane-helix structure, so pulling it out of the membrane would
leave a massive hole in the middle of the membrane, which is filled with
water and not lipids. I find it hard to believe this would work and give a
reliable result, so I turn to you to ask for opinions/alternatives!

Thanks in advance.

Victor

On 24 February 2014 14:13, sojovictor <sojovictor at gmail.com> wrote:

> Thanks so much, Justin!
>
> Your comments and paper are very helpful indeed. With "by eye" I meant I
> just need to know whether one is bigger than the other, but you're complete
> right: no need to speak in qualitative terms when I can quantitatively
> determine DeltaDeltaG.
>
> Thanks again!
>
>
> Victor Sojo
>
>
>
>
> On 23 February 2014 17:37, Justin Lemkul [via GROMACS] <
> ml-node+s5086n5014747h97 at n6.nabble.com> wrote:
>
> >
> >
> > On 2/23/14, 11:54 AM, sojovictor wrote:
> >
> > > Thanks, Justin! That's really helpful indeed.
> > >
> > > You are correct, I want to know what's the energy change in replacing
> > one
> > > lipid with the other, hypothesising that going to the "wrong" lipid
> will
> > > imply an energetic cost.
> > >
> > > Via umbrella sampling, I would thus:
> > >
> > > 1) Set up a full system with protein, lipids, solvent, and ions.
> > > 2) Pull the protein perpendicularly out of the membrane and into the
> > solvent
> > > (which means I'd need a lot of solvent in the direction of the pull,
> > such
> > > that there's always enough space to fit the protein and still avoid
> > boundary
> > > interactions, as you explain in you tutorial, thanks!).
> > > 3) Do the exact same thing with the other system, independently.
> > > 4) See just by eye what the difference is and hope it matches my
> > prediction.
> > >
> >
> > I don't understand what "by eye" means here.  You'll get a free energy
> > difference between the embedded and solvated states, i.e. the
> > binding/insertion
> > energy.  There's nothing qualitative about that.  That's deltaG for a
> > particular
> > lipid type, and the deltadeltaG is simply the difference between the two.
> >
> > > Now, my question about using umbrella sampling for this purpose: is it
> > > reasonable to use the whole membrane (say, the group of lipids) as my
> > > immobile reference? In your tutorial you use a chain, in which all
> > members
> > > are covalently bound to each other, so I didn't know whether you could
> > use a
> > > group of independent molecules instead. I assume it will be fine, then.
> > >
> >
> > Don't assume from the tutorial that you need an immobile reference.  The
> > fact
> > is, you don't.  You need to define a sensible reaction coordinate that
> > describes
> > embedded and water-solvated states.  Neither of those intrinsically
> > requires any
> > sort of position restraint.
> >
> > What I had was a very specific case, and if you read my paper from which
> > the
> > tutorial was derived, you will find that the restraints there are used
> for
> > a
> > special purpose to mimic fibril stability.  That's not the case in most
> > umbrella
> > sampling runs.  During the generation of configurations, you may need
> some
> > restraints to prevent perturbation of the bilayer structure, but that
> > depends on
> > how you generate those configurations.  A more pertinent example would be
> > http://dx.doi.org/10.1021/jp202217f.
> >
> > -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
> >
> > [hidden email] <http://user/SendEmail.jtp?type=node&node=5014747&i=0> |
> (410)
> > 706-7441
> > http://mackerell.umaryland.edu/~jalemkul
> >
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