On 6/1/15 12:13 PM, MPI wrote:
I wonder when it is appropriate to add NH3 into the system and how to
setup the control of temperature coupling in thermostats.
For example,
1. add NH3 first with the protein and then embed protein-NH3 into the lipid
or
2. embed the protein into lipid with an equilibration, followed by
adding NH3 into the system
If you want NH3 to pass through the channel, I'd say (2), more or less, but
really you should add NH3 as a cosolvent as part of the equilibration. Add the
NH3 in the box, add water, and equilibrate.
If choosing (2), what is the concern ?
Why adding NH3 as part of water_and_ions after protein-lipid is
equilibrated already ?
Choosing (2), I have to go through equilibration twice.
No you don't. You add NH3 into the box, then solvate with water. See
http://www.gromacs.org/Documentation/How-tos/Mixed_Solvents
I'm saying that (2) is in general more logical for your purpose (as I understand
it) but you don't do two separate equilibrations. Moreover, it is unlikely that
you'll be able to find space in an equilibrated layer of water to insert NH3
molecules.
Hi Justin,
Thank you very much for the details.
Also, if the substrate is a very small ligand, is the protocol the
same ? Namely, adding a new substrate AFTER protein-lipid is
equilibrated. Then perform another equilibration for the substrate +
protein-lipid.
This is context-dependent. If you want to simulate a protein-ligand complex in
a bilayer, you add the ligand first into the protein (crystal structure,
docking, etc). If you want to observe partitioning from bulk solvent of the
ligand into the protein's binding site, then it's the same. Put the required
number of ligands into the box where the solvent will be, then add the solvent
(water).
If I understand this correctly, you actually suggested adding a ligand
BEFORE adding the solvent and BEFORE the protein is embedded into
lipid bilayer. Is this correct ?
I am concerned about the sequential order of adding a substrate and
embedding a protein into a bilayer.
Which one goes first ?
1. Protein into bilayer
2. Add ligands/cosolvent
3. Add water
4. Add ions
Also, if the substrate has a charge, which order is preferred ?
Charge shouldn't affect the protocol.
Did you mean when adding a new substrate, eg, NH4+ or Ca2+ into a
protein-lipid system, one has to remove all ions and water in the
equilibrated protein-lipid system, put back ions and water again and
finally equilibrate the new system right after ?
Or just build it in sequence from scratch without having to remove water and
ions. That's what I'm suggesting above. The cosolvent/ligand/whatever is
always added before the water. It's easier and faster in practical terms,
Before the water, it means "you add ligand at the very beginning
BEFORE protein is embedded into bilayer, correct ? "
No, see above.
If so, what about the temperature coupling ?
(1) tc-grps = Protein DPPC water_and_ions_and_LIG
or
(2) tc-grps = Protein_LIG DPPC water_and_ions
This is tricky. You have a freely diffusing species that will pass into/through
the protein. So at some times it may be part of the solvent, sometimes it might
be bound to the protein. I can't predict what the differences might be here.
Strictly speaking, multiple thermostats aren't correct, but are common,
especially in such heterogeneous systems.
It seems to me if LIG = NH3/NH4, then (1) is preferred but if LIG is
a small drug "MOVING" along the channel, dose (2) make sense ?
or (3) tc-grps = Protein DPPC LIG water_and_ions ?
because if you have to remove solvent, then what was the point of the initial
equilibration?
The initial equilibration is for inserting protein into the bilayer.
One can add any substrate afterwards without worrying about the
process of inserting a protein into bilayer. Dose it make sense to you
?
I suppose you can do this if you need to. Depends on how you're inserting the
protein, I suppose, and how much equilibration you intend to do before
introducing your ligands/cosolvents.
-Justin
--
==================================================
Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow
Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201
jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul
==================================================
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