[gmx-users] Free energy perturbation of Cu(I) binding

[David Mobley]

Hi,

> Thanks David, But if I just remove the Copper atom and do the
> simulation as copper is charged there would be sudden change in
> electrostatics and the protein started unfolding when I ran the
> simulation for 10ns. So I thought perturbing the charge by little
> every time I can get a structure with more reasonable than artifacts.
> Can you please correct me if I am thinking in a wrong way.
> abhigna

The other thing I would remark in response to this is that you may
want to think carefully about equilibration and convergence.

Here's what I mean. There is in principle nothing wrong with
drastically changing the electrostatics as long as your system is able
to reach equilibrium again after you do this. Changing the
electrostatics more slowly might have the same end result (or it might
not).

If  you don't believe your system will unfold in the absence of the
copper ion, you can do what others suggested and apply some position
restraints to the protein for  awhile to help it "equilibrate" in the
absence of copper without unfolding. Or you can do what you suggest.
If you want to do what you suggest I'd just make the B state charge on
the copper ion be zero and use a small lambda step with the free
energy code turned on using linear scaling. Then in a time-dependent
way over the course of your simulation, turn the charge to zero. Once
that's done, just delete the copper ion and proceed.

However, at some point, you'll need to make sure you explore the
energy landscape enough to establish some level of consequence that
the preferred state for the protein in the absence of the copper isn't
the unfolded state (I'm not talking experimentally, here -- I'm
talking about with your particular parameters).


David Mobley, Ph.D.
Assistant Professor of Chemistry
University of New Orleans
New Orleans, LA 70148
dlmobley at uno.edu
Office 504-280-6445
Fax 504-280-6860



> On Tue, Feb 3, 2009 at 6:13 PM, David Mobley <dmobley at gmail.com> wrote:
>> Perhaps this is obvious, but typically you only want to do free energy
>> perturbation if you are interested in computing a free energy
>> difference. If you are merely interested in structural properties of a
>> different system (in this case, the protein without the copper there)
>> you can simply make the change to the system (here, remove the copper
>> atom) and run long enough for it to reach equilibrium.
>>
>> On Tue, Feb 3, 2009 at 3:55 PM, Polavarapu, Abhigna
>> <polavara at indiana.edu> wrote:
>>> Hi all,
>>>        Thank you for the help till now and I successfully generated the forcefield Cu(I) binding protein. Now I wanted get the structure of non-copper bound form which I think I can do by perturbing the charge on Cu(I) and even perturbing the bonded and nonbonded parameters. Is there a way I can do this with Gromacs and when I read through chapter five I could understand the way it is done but I am not really confident about the protocol of getting the good structure for nonbonded protein with Cu(I). Can any one tell does this method works for this kind of situation where I have a Copper bound protein and by perturbing its bonded and nonbonding interactions one could arrive at the nonbonded protein structure and the energy difference. Thanks in advance.
>>> abhigna
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