Re: Overestimated PMF

From: Giacomo Fiorin (
Date: Mon Jun 17 2013 - 10:10:10 CDT

Hello Felipe, are you summing the free energies from two separate
calculations where you detach only one domain while keeping the other
domain still bound?

If you did that, this would explain why the discrepancy: those two terms
are not necessarily additive.

The correction would be to finish either simulation by also detaching the
bound domain, and letting the entire protein go far enough from the DNA for
all interactions to vanish.


On Mon, Jun 17, 2013 at 10:43 AM, Felipe Merino <> wrote:

> Dear all,
> I know this is a little bit off topic but i think somebody could help us
> here. We have been doing some umbrella sampling simulations to calculate
> the binding free energy of a protein-DNA complex. We are using the minimal
> interatomic distance as reaction coordinate. The thing is that the protein
> has two domains and we are only pulling them separately, so in the end we
> have always an endpoint with the other domain still bound (that was
> planned). In the end, the binding free energies are much higher than
> expected (around 25 kcal/mol). The point is that it sounds to me that there
> should be a correction on the PMF to account for the "confinement" of being
> bound to the other (still attached) domain (very much line in the case
> where you restrain the ligand when doing FEP annihilation) but i am not
> sure if this is correct. Any insights for this will be highly appreciated.
> Best
> Felipe

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