Re: [AMBER] From PMF to free energy of binding

From: Andreas Tosstorff <>
Date: Tue, 24 Jan 2017 16:42:39 +0100

Dear David,

thank you for the input! What other explicit solvent methods would you
rather suggest to calculate free energies of binding for protein-ligand
and protein-protein complexes?

Kind regards,


On 01/24/2017 02:46 PM, David Case wrote:
> On Mon, Jan 23, 2017, Andreas Tosstorff wrote:
>> I saw different approaches on how to calculate free binding energies
>> from PMFs in the literature:
>> Some took the difference between the PMF curve's energy minimum and the
>> value at the maximum distance.
> This is certainly a pretty drastic approximation, since the width of the
> "well" containing the bound ligand can be just as important as the energy at
> the bottom of the well.
> If you know the PMF accurately (a big "if") then you can compute the
> probability of the system being at any particular value of the progress
> variable. Next: figure out a dividing point, so that you are willing
> to call configurations that are on one side of the dividing point "bound" and
> on the other side "unbound". Finally, compute an equilibrium constant by
> dividing the fraction bound by the fraction unbound, and convert this
> equilibrium constant to a standard free energy in the usual way.
> [Caveat: above is a bit oversimplified for ligand binding, since PMF's are
> generally computed with a *single* ligand and a single receptor; you have to
> make the usual standard state corrections to account for the concentration
> dependence.]
> Other methods use different (often more efficient) ways to estimate the work
> required to dissociate the ligand from the receptor. But the procedure
> outlined in the previous paragraph is the only one (I think) that fits the
> description of computing the binding free energy *from* the PMF.
> ....dac
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M.Sc. Andreas Tosstorff
Lehrstuhl für Pharmazeutische Technologie und Biopharmazie
Department Pharmazie
LMU München
Butenandtstr. 5-13 ( Haus B)
81377 München
Tel.: +49 89 2180 77059
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Received on Tue Jan 24 2017 - 08:00:02 PST
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