Re: new NAMD user ABF setup question

From: Jérôme Hénin (
Date: Wed Jun 02 2010 - 09:53:05 CDT


On 2 June 2010 03:15, Felipe Merino <> wrote:
> Hey,
> I have a question in this regard. A couple of weeks ago in our lab we were
> talking about the same topic since a PhD student here wanted to simulate the
> effect of some interface mutations in some dimers, Since these are obligated
> dimers, the alchemical way had the problem of not having an adequate model
> for the free monomers (since on their own they are essentially unfolded - i
> guess one could try to obtain a model anyways using something like replica
> exchange, but it would be way too expensive in terms of computation time).

What this tells me is that the binding/unbinding process also has a
folding/unfolding component. Therefore, any method you use will only
be as reliable as it samples this complex conformational relaxation.
There is no miracle: alchemical and PMF calculations will hit the same

> So, finally we concluded that no PMF calculation would give good results in
> a reasonable time and  we arrived at the conclusion that an SMD simulation
> could be appropriate for at least a qualitative result. However, isn't this
> approximation considering that most of the difference in binding free energy
> comes from  enthalpic contributions? I ask because i guess this is not
> trivial for a system as big as a protein when, even for small moelcules
> sometimes the binding free energy is considerably determined by entropy.

Indeed. Since the full process is too complex to sample, you need
simplifying assumptions. Using irreversible SMD and going qualitative
will work (i.e. it will always give *some* answer), but the
assumptions are not well-defined (they would be something like
"neglecting the slow-relaxing contributions makes no big difference
because the errors from the wild-type and mutant cancel out"). One
suggestion I have is the following: since sampling the unfolding is
very difficult, you could decide not to compute that contribution, and
perform alchemical FEP with soft restraints on the overall
conformation of each monomer. Then if you are bold, you could even try
evaluating the restraint contribution by computing PMFs (e.g. for an
RMSD coordinate) for the monomers: this could at least give you an
idea of how different the WT and mutant behaviors are.


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