[gmx-users] Metal-Protein interactions

[Justin Lemkul]

On 11/28/17 1:00 PM, RAHUL SURESH wrote:
> On Tue, 28 Nov 2017 at 7:14 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>
>>
>> On 11/28/17 4:54 AM, RAHUL SURESH wrote:
>>> I am trying to simulate a metal-protein interaction using gromacs 2016
>>> package and charmm36 ff.
>>> I have prepared the initial pdb by performing an oniom calculations
>> between
>>> protein and metal (at various positions) using gaussian 09 and chose the
>>> structure with maximum binding energy. The metal ion is bonded to oxygen
>>> atom of His residue. Having a look at gro file after each step
>> That's unusual; His typically coordinate metals via their delta or
>> epsilon N atoms.
>>
> Sorry that I pronounced wrongly as oxygen.. regret the inconvenience.
>
>>> (protein.gro, em.gro, nvt.groand npt.gro) the distance between metal  ion
>>> and the oxygen atom keeps increasing starting from 2.06 to 2.69. Over the
>>> course of simulations for 10ns, the metal ion is away from the protein.
>>>
>>> What can be done to have the metal ion restrained at its position? Or if
>> I
>>> extend the simulation will the metal ion find its appropritae position
>>> during the course time?
>> Unlikely. This is a fundamental issue with classical mechanical force
>> fields approximating ion interactions very poorly, particularly in the
>> case of multivalent and/or transition metals. There are many effects
>> like polarization and charge transfer that simply can't be modeled. You
>> can apply distance restraints (or actual covalent bonds), NBFIX LJ
>> parameters, etc.
> while restraing the metal ion, it arise an error stating that an atom can
> not be mentioned in two groups.
> Tc grps = protein_cu water_and_ions.
> Cu will already be mentioned in ions.

It should be grouped with the protein; a coordinated metal is 
functionally part of the protein and should be treated as such. It makes 
no sense to couple it to the solvent thermostat.

> and that may be enough to preserve the binding pose. In
>> reality, one would have to reparametrize any ligating residues because
>> the charge distribution on the ion and anything coordinating it is not
>> at all what the standard force field uses.
> Reparameterize.? Means I have to add additional parameter file to the
> charmm36 ff after interacting with metal ion.?

It means you would have to derive new residue definitions, but a QM/MM 
approach is probably superior.

>
> Also Justin, what if I can manually add a bond between N of HIS and metal
> ion with most appropriate bond length ..?
> (To avoid complexity if it works)

Yes, that is a possibility, but again you will have to do some QM work 
to properly parametrize the geometries and vibrational frequencies for 
the new bonded parameters (which then include angles and dihedrals). 
Cu2+ is a difficult ion to deal with, though, so this may be 
surprisingly laborious.

-Justin

-- 
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Justin A. Lemkul, Ph.D.
Assistant Professor
Virginia Tech Department of Biochemistry

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