Re: [AMBER] MM/PBSA calculations

From: Ray Luo, Ph.D. <>
Date: Fri, 20 Apr 2012 16:46:29 -0700

Just a comment on this ... use of protein dielectric constant other
than 1 is a reasonable way to consider the polarization effect that is
absent from the underlining force field or the limited sampling in the
MD simulations. Ideally, we should use polarizable force fields for MD
and MMPBSA calculations, but we still have to wait for these types of
force fields to mature for routine applications.

If you want to use the strategy, you'll need to use the same protein
dielectric constant for both the PB part and the Coulomb part to be
consistent as what Hou et al did. This can be demonstrated with a
thermodynamic cycle for the binding calculation, though I have to say
that it is not trivial to show.

You can say that this is an extension of the original MMPBSA approach.

All the best,

On Fri, Apr 20, 2012 at 5:06 AM, mish <> wrote:
> Dear All,
> I have a couple of question related to changing internal dielectric
> calculations in MM/PBSA calculations. In Tingjun hou et al JCIM 51,1,69-82
> (2010) authors writes that they investigate suitable solute dielectric
> constant to cal calculate polar solvation free energies. But if I look at
> the values I get a feeling that they used higher dielectric constant also
> to calculate electrostatic contribution to the gas phage energies.
> Therefore, in reality it was energy is not the gas phage energy but energy
> in some organic solvant with diel 2, 3, ..4. I would like to know whether
> it is not something which is beyond the definition of MM/PBSA method.
> Changing Internal dielectric constant for PB part seems to justified well
> in the paper. Can you please comment on this ?
> Another question is related with a statement in MM/PBSA tutorial that is
> "sum of the electrostatic solvation free energy and MM electrostatic energy
> tend to approximately cancel each other out ( so PBELE/GBELE close to Zero)
> which should be much smaller than the contributions to it".
> I am facing an issue and I think this is somehow related to this fact. I
> did MM/PBSA calculations for couple of ligands (of different size) with a
> same receptor and what I observe is for small ligands, higher internal
> dielectric constant (about 3 or 4 for both Emm and Esol) provides dG in
> good agreement to the experiment. So the binding energy increases from -33
> (for diel=1) to -20 (diel=3).  Whereas for large ligands, increasing
> internal dielectric constants for decreases binding energy (-34 (intdl=1)
> to -36 (intdl=4)). So for large ligands internal dielectric constant =1 is
> the one closer to experimental value. The origin of such difference can
> arises from PBELE values form both cases. Changing internal dielectric
> constant from 1 to 2, 3,4 .. changes PBELE  of small ligands from -8.0 to
> -2, whereas for larger ligands it varies from  1.5 to  -0.1. I really do
> not understand what is the origin of two different behavior in binding
> energy for same binding site. In case of large ligands some part of the
> ligand interacts better in water whereas small ligands are inside the
> cavity and do not interact with water.
> ..Mish
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