Hi Andreas,
In my opinion, the difference between Woo and Roux's approach and the other
one you mentioned ("difference between the [PMF] curve's energy minimum and
the value at the maximum distance") is that the former is rigorously valid,
whereas the latter may have significant errors depending on the specific
receptor/ligand and the restraints involved.
When some sort of biasing restraint is used to compute a free energy, you
should always be certain that the entire free energy pathway is
considered. In the simplest case, let's imagine that I use a single
distance restraint between a ligand and the receptor to move the ligand out
of the binding pocket over a series of sampling windows. To be rigorously
correct, I should first compute the work (aka free energy) of attaching the
distance restraint between the ligand and receptor, and then the work to
move the ligand away from the receptor, and finally (if I need to compare
with experiment), the work to place the ligand at standard concentration (1
M). In some cases, the work of attaching the restraint will be small and
possibly negligible, but I would make that assumption very carefully.
We have been developing an approach in the Gilson lab called
Attach-Pull-Release which is a similar in flavor to Woo and Roux's
approach. See this paper
<
http://pubs.acs.org/doi/abs/10.1021/acs.jctc.5b00405> and a recent tutorial
<
http://ambermd.org/tutorials/advanced/tutorial29/> for more info.
Best,
--Niel
On Mon, Jan 23, 2017 at 9:03 AM, Andreas Tosstorff <
andreas.tosstorff.cup.uni-muenchen.de> wrote:
> Hi all,
>
> I saw different approaches on how to calculate free binding energies
> from PMFs in the literature:
>
> For example in Woo and Roux Paper from 2005, called "Calculation of
> absolute protein–ligand binding free
> energy from computer simulations" they used a set of equations to
> calculate different contributions to the total free energy.
>
> Some took the difference between the PMF curve's energy minimum and the
> value at the maximum distance.
>
>
> So what's the best approach to calculate free energy of binding from a PMF?
>
>
> Kind regards,
>
>
> Andreas
>
> --
> M.Sc. Andreas Tosstorff
> Lehrstuhl für Pharmazeutische Technologie und Biopharmazie
> Department Pharmazie
> LMU München
> Butenandtstr. 5-13 ( Haus B)
> 81377 München
> Germany
> Tel.: +49 89 2180 77059
>
>
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Received on Mon Jan 23 2017 - 12:00:02 PST
