[gmx-users] Re: peptide & bilayer sims

[Graham Smith]

> now planning to insert a alpha helical peptide in the headgroup
> region of the equilibrated bilayer. I was wondering if Drs. Lindahl,
> Van der Spoel, I didn't want to solvate the peptide as it would
> affect it's structure before I place ina equilibrated/hydrated
> bilayer. 

> I have a similar problem with bilayers . i don't know how
> put my peptide i=

> Do either of you have any suggestions on how I could decrease the
> potential energy of my peptide without solvating it? DMSO...could
> that be an option?????? 


Reading between the lines, I take it that you have one of those
antimicrobial peptides (cecropins or something?) that form amphipathic
helices with lots of lys on one side and seem to bind to lipid
bilayers, esp. those with lots of negative phospholipid, carpeting the
surface,  and disrupt them or make holes in them. I did a little bit
of work on them a couple of years ago but never published anything. 

It seems likely that the conformation of the peptide in water will be 
different to its conformation when it is half-buried in the head-group
region of the bilayer, and so you want to get it in the "right"
conformation before trying to insert it. But I don't think it's
possible to know what that conformation is until the peptide is
inserted; then eventually it should insert itself to the depth
where it is happiest, and its conformation should relax; but in
practice the side chains will get tangled up with the lipid  
head groups and I would guess that it will take hundreds of ns 
for anything to happen. So this is a very hard problem. 

Maybe DMSO is a good idea, or any solvent with a lower dielectric
constant than water, if you think the side chains of the peptide
should curl up a bit rather than being extended. A low dielectric
solvent should also help if your peptide is losing helicity in water.
But you're still only approximating the headgropu environment. 

If you just want to go ahead and insert it anyway, you could use my
gromacs-modified-to-make-a-hole thing from the contributions page
(though I'm hesitant to suggest this after the problems some other
people have had). You don't have to make a hole right through the
bilayer: if you align your peptide with where you think it should be
in the headgroups, then make a molecular surface for it, you'll be
able (with luck) to drive the headgroups out of that volume, and so
make a "furrow" in the surface that you could drop your peptide into.

An idea that just occurs to me, if you have a nice big computer (they 
always used to at Edinburgh when I was there), is that
you could start from a randomized mixture of lipid and water.
Sievert-Jan Marrink did this a year or so ago and got bilayers forming
spontanously in about 50-100 ns. If you added your peptides to
the mixture you might find that they inhibited the formation of the
bilayers.  

-Graham 

########################################################################

Dr. Graham R. Smith,
Biomolecular Modelling Laboratory,
Cancer Research UK,
44 Lincoln's Inn Fields,
London WC2A 3PX,
U.K.
Tel: +44-(0)20 7269 3348
email: graham.smith at cancer.org.uk
URL: http://www.bmm.icnet.uk/~smithgr