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

From: Jérôme Hénin (jhenin_at_ifr88.cnrs-mrs.fr)
Date: Wed Dec 08 2010 - 16:16:58 CST

Dear Ajasja,

On 8 December 2010 17:31, Ajasja Ljubetič <ajasja.ljubetic_at_gmail.com> wrote:
> Dear all,
> I would like to explore the conformational space (ie the free energy
> landscape) of the side-chain of a spin label (MTSSL) in water and in the
> membrane. The side chain has five dihedral angles (chi1 to chi5). I'm
> thinking of using ABF for this purpose, but the following questions arise:
>
> What would be a sensible value for the fullSamples value? (Since lipid tails
> may relax slowly, probably something in the range of 500-1000).

That is, I think, a point of detail compared to the other questions.
The key question is choosing the right reaction coordinate space, as
discussed below.

> The first dihedral angle is composed of two backbone atoms. If I restrain
> the backbone, does the first chi angle still count as unconstrained (does it
> fulfill the requirements for a well defined ABF colvar)?

Yes. Restraints do not interfere with ABF (even if they are called
"constraints" in NAMD for historical reasons).

> Would metadynamics be a better choice? What would be a good hillHeight?
> (about 1/tenth of the highest torsional energy barrier).

Metadynamics might be a better choice for a high-dimensional
landscape. One classic metadynamics study computed a 6D map, although
there was not much hope of it being converged. That study went on with
a more quantitative one-dimensional calculation:
http://www.pnas.org/content/102/19/6755
Dealing with the 6D PMF probably presented the author with interesting
technical hurdles, chief among which visualizing the data!

> And some more philosophical ones:

These are good. They are the right ones to start with :-)

> What happens in the conformations where the side chain overlaps the
> backbone? The free energy there is really high due to VDW contacts. Does ABF
> push the sidechain through the backbone?

I would not expect that to happen. In practice, because of finite grid
resolution, ABF biases are rarely steep enough to push atoms through
walls, especially in multidimensional simulations, where alternate
pathways around the obstacle are available.

> Is it even feasible to explore a 5D space using ABF? I'm thinking of using a
> bin width of either 15 or 30  degrees (~250k or 8M bins).

I would recommend against it. On top of the impracticality of handling
the 5D data, getting adequate sampling would be a nightmare. ABF is
not very resilient to poor sampling, probably less so than
metadynamics, which offers the option of a quick non-equilibrium
exploration of a large landscape.

The question you should consider is: do you absolutely need to work in
this 5D space? Are all these degrees of freedom equally significant?
Is the chain fully flexible? Are there intrinsic conformational
restrictions? Do you have prior knowledge of key conformations? The
ideal situation would be for you to find a 2 or 3D space that might be
a good enough descriptor. For a flexible chain, I would start with
some RMSD and radius of gyration. You can first experiment with very
quick and inexpensive vacuum simulations, just to get a better idea of
what coordinates will make the molecule explore its conformational
space.

Best,
Jerome

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