On 2/23/14, 10:36 AM, sojovictor wrote:
Dear all, I would like to find the difference in the energy of binding or insertion of a protein into two different types of phospholipid membranes (plus water and ions). i.e., my hypothesis is that the energy should be lower with one type of membrane than with the other. I have considered an alchemical transformation from one system to the other, gradually replacing a lipid with the other one, but I've been unable to find any example of people switching off something as large as a protein; all the examples I find are of ligands, single aminoacid residues, or solutes, much smaller particles than what I'm attempting. This makes me wonder whether what I'm planning even makes sense, or if such a simulation would never converge or give reliable results due to the large vacuum in the middle of the membrane created upon switching off the protein. Taking guidance from Mobley,Chodera & Dill's 2006 paper on J.Chem.Phys., and from Justin Lemkul's tutorial, I've devised the following, potentially impossible, thermodynamic cycle: <http://gromacs.5086.x6.nabble.com/file/n5014735/Thermodynamic_Cycle.png> Clockwise from the top left, I would do this in seven steps: 1) (Position?)Restrain the protein in the first membrane. 2) Decouple coulombic interactions in the protein (I assume annihilating would not be a good idea here). 3) Decouple Lennard-Jones interactions in the protein. This will leave me with a system that is effectively equivalent to an independent fully-restrained/non-interacting protein, and a free membrane. 4) Change membrane to the second type, keeping both interactions off and protein restriction on. 5) Switch on Lennard-Jones interactions. 6) Switch on coulombic interactions. 7) Remove protein restriction. I believe it wouldn't be necessary to calculate energies for the protein in solution, since my interest is not the free energy of binding to one membrane, but the change that would be experienced upon changing from one membrane to the other.
This sort of contradicts what you said in your first sentence. I take it you're interested more in a transfer free energy between the two lipid types?
Now, my initial impression is that this would not work, but I can't think of anything better, so I'd very much welcome input. Alternatively, I have considered umbrella sampling: I would pull the protein out of one of the membranes, separately do the same with the other membrane, and see what's the difference, but I can't think of anything I could keep as the reference system for the centre of mass (the membrane does not seem to be a good idea).
Why not? This seems to be the clearest approach to me, which also has the upside that it avoids the possible unphysical outcomes of trying to alchemically transform a protein. The complex system of restraints that would be necessary would, in my mind, seriously complicate the interpretation of the outcome. A one-dimensional reaction coordinate along the normal to the bilayer seems intuitive and straightforward to calculate.
-Justin
In general, any advice on how to proceed with this calculation, a reference to the literature, or wild guesses, would be very welcome! Thanks, all. Victor Sojo -- View this message in context: http://gromacs.5086.x6.nabble.com/Binding-energy-of-membrane-protein-to-the-membrane-lipids-tp5014735.html Sent from the GROMACS Users Forum mailing list archive at Nabble.com.
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