[gmx-users] membrane protein simulation

[chris.neale at utoronto.ca]

> I am trying to set up an ED experiment with the low resolution structure of a
> membrane protein in the hope of generating NMR-like structures.

By ED do you mean essential dynamics? I haven't done that, but it  
seems to me that the system setup should be identical to regular MD.

> From what I have read until now, I know that I should either  
> restrain the transmembrane domain of the enzyme (or simulate without  
> it), or do the simulation within a bilayer membrane. The choice is  
> somewhat complicated by the
> fact that the active site of the protein (which is of interest to  
> me) is quite
> close to the transmembrane domain. So I think it would be safer to  
> simulate with the membrane, or is there a simpler solution ?

I would recommend a full membrane. If you don't have time to  
explicitly simulate the membrane, you can put harmonic restraints on  
the heavy atoms of the side chains of the aromatic residues that would  
usually interact with the lipid headgroups and put a water droplet  
over the top of the active site. As for how to determine the position  
and orientation of your protien in the membrane, see for example 1)  
Kandasamy and Larson Biophys. J. Vol 90 April 2006 2326-43; 2) Lomize  
et al, Protein Sci. 2006 15:1318-33.

> Also, I am quite new to membrane protein simulation and I would like  
> to know how the bilayer type is chosen ? (My protein is a eukaryotic  
> enzyme naturally bound to the endoplasmic reticulum).

I determine my bilayer type based on 4 questions, in approximately the  
order shown:
A) What would the in vivo situation be?
B) What is the hydrophobic length of the protein?
C) What parameters are available?
D) What starting coordinates are available?

For the Rat liver ER, you're looking at 20% PE, 14% PI/PS, 53% PC, 4%  
sphingomyelin, 10% unknown; and Carbon tails between 10-20% populatino  
for each of C16:0 C18:0 C18:1 C18:2 C20:4 C22:6 over PC and PE  
(Davison & Wills, Biochem. J. 1974, 140, 461-8) and a hydrophobic  
length of about 28A (Lomize et al, Protein Sci. 2006 15:1318-33).  
Since simulated membranes tend to be too thick according to the  
current deconvolution of Xray scattering data, and given the specifics  
listed above, I would personally use DPPC as an ER mimetic. You can  
get starting coords and parameters for this from Dr. Tieleman's  
website: http://moose.bio.ucalgary.ca/

Chris