Using ABF to explore the conformational space of a spin label attached to a membrane protein

From: Ajasja Ljubetič (ajasja.ljubetic_at_gmail.com)
Date: Wed Dec 15 2010 - 07:21:54 CST

Dear Jrme and Branko,

Sorry for the late reply, I have been to a conference (a
quite enjoyable one, although, as always, the schedule was too busy to hit
the sauna :)

Well, yes, the first question is a technical detail. I was wondering if I
should start from practical to the philosophical or in reverse order.

Regarding the presentation of a 5D space. It is indeed a problem. My
current<http://www.ijs.si/ijs/dept/epr/ajasja/mails/mtssl/5D.png>solution
is to draw all the 2D projections as a density plot (here I'm
showing the histogram of angles during the simulation, but a 5D PMF could
be presented in the same manner). But this is not very useful, except
perhaps for spoting differences between two such sets of projections.

Regarding the overlap of the sidechain with the backbone. If I
understood correctly then all the bins along the given reaction coordinate
are supposed to be evenly sampled. But If the backbone is fixed and if using
15 degree bins, then such
conformations<http://www.ijs.si/ijs/dept/epr/ajasja/mails/mtssl/overlapMTSSL.png>are
inevitable (otherwise the sampling is not uniform).
The backbone is green and the label is shown in red. The angles are -22,
123, -80, -87, 95 degrees.
Inside the width of the bin such overlap can not be avoided. So does this
mean that such bins are simply not sampled?

I have knowledge of (1D) relaxed dihedral
scans<http://www.ijs.si/ijs/dept/epr/ajasja/mails/mtssl/mtssl_dihedral_potentials.png>around
each single bond. With the added complication, that the Chi5 scan is
very dependent on the value of Chi3. For the Chi3 angle there are two
distinct minima, so it should perhaps be possible to split this in to two
(or few) 4D runs.
I haven't really thought about choosing any other collective variables. The
projections of the CA-O could be interesting, but as pointed out by the above
reference <http://pubs.acs.org/doi/full/10.1021/ct100413b> "simple, yet
hand-picked, collective variables, as a set of chosen distances, turn out to
miss some relevant features of the free energy surface. " Since I don't yet
know what the relevant features of my landscape are, this could be a
problem.

This is not directly connected, but it has been buging me anyway:
Could a 1D relaxed dihedral scan be done using NAMD's CV module? (if the CV
module is active during minimization this could be done using harmonic
restraints and SMD.
A relaxed dihedral scan is basically the change in potential energy (dU)
with regard to the chosen dihedral angle. By running an ABF on the same
dihedral one obtains the change in free energy (dG).
So is the difference between the two equal to TdS? (Using G = U + pV - TS
and neglecting the pV term and any electrical work at constant temperature)--001636c5c20425f137049772d20b--

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