Re: [AMBER] [Sender Not Verified] About polar solvation term in MMGBSA decomposition results

From: Steinbrecher, Thomas via AMBER <>
Date: Wed, 14 Jun 2023 08:47:05 +0200

Hi Xiangyu,

first of all, Id caution into reading too much into these values, you are
comparing net contributions to binding by subtracting force field
electrostatics energies (a big number from an approximate interaction
model) from implicit solvent electrostatics (a big number from a different
approximate interaction model) so the (small) net contribution suffers from
a fairly big error. Getting such values into the sub-kcal accuracy range
they would need to be in to study subtle changes in bound complexes is not
an easy thing to get right.

Besides that, I dont find your first observation problematic. I believe
that a charged or polar protein ligand interaction can be both very stable
and less favorable than a corresponding protein-water interaction. The
interaction is stable because it is 'the best the ligand can do' without
unbinding. FEP tells you that removing the polar group is unfavorable
because the ranking of binding partners to this one protein residue may be
water > ligand-OH > ligand-CH3. Directional polar interactions like Hbonds
and salt bridges may often contribute little to net binding of a ligand,
but they may be crucial to provide selectivity for the binding partner.

Kind Regards,


On Wed, Jun 14, 2023 at 3:58 AM xiangyu via AMBER <> wrote:

> Hello Amber Users,
> I used mmgbsa to analyze the importance of each of binding residues in
> binding of a ligand to a protein. I have some issues understanding some of
> the results. The Delta polar solvation terms (complex –ligand-protein) of
> the residues participating in forming hydrogen bond/ionic bond with ligand
> is more positive than the Delta electrostatic term, indicating that when
> forming the complex, the increase change in solvation energy compensates
> the decrease of electrostatic change. Does it mean that forming hydrogen
> bond/ionic bond is in fact unfavorable in binding the ligand to protein?
> Apparently to me, this is counterintuitive, since from both crystals and MD
> results, those hydrogen bonds are very stable. And in a FEP test, if I
> remove the polar group of ligand that participate in the H-bond, the FEP
> become very positive. Also, I noticed that electrostatic energy terms of
> LYS and ARG no matter interacting with ligand or not are always positive
> while the polar solvation terms are always negative., And for GLU and ASP,
> it is opposite. I'm confused about this result. I used the same gb setup
> in tutorial (igb=5 saltcon=0.1)
> total van der waal electrostatic polar solvation nonpolar solvation
> GLU 231 -0.602 0.050 -1.295 0.031 -46.182 0.076 47.09 0.07 -0.21
> 0.001 TYR 223 -0.366 0.020 -0.421 0.023 -3.557 0.030 3.73 0.02
> -0.12 0.001 PHE 226 -2.8406 0.0320 -2.8299 0.0270 -5.4634 0.0422
> 5.7657 0.0293 -0.3130 0.0017
> Thanks in advance for any help
> _______________________________________________
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*Dr. Thomas Steinbrecher*
Principal Scientist CADD
Roche Pharma Research and Early Development
Roche Innovation Center Basel
F. Hoffmann-La Roche Ltd
Bldg. 092/3.92
Grenzacherstrasse 124
4070 Basel
Phone +41 61 682 1319
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Received on Wed Jun 14 2023 - 00:00:04 PDT
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