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

Thu May 8 23:09:27 CEST 2014

On 5/8/14, 3:38 PM, Victor Sojo wrote:
> 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!
>

The bigger question is: is what you are seeking to simulate reasonable?  There 
is no reason to believe that a 7-TM helical protein will insert into a membrane 
from a folded state in the aqueous medium, or that it will remain stable in 
water.  In fact, that doesn't happen.  So you're quite right that it will 
require massive reorganization of the membrane to do this, probably to the point 
that it's not practical or reliable.  It seems that you may need to re-think 
your approach a bit.

-Justin

> 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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-- 
==================================================

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

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