Re: [AMBER] positive free energy

From: Vlad Cojocaru <>
Date: Wed, 20 Aug 2014 22:32:03 +0200

Sorry, I send the email too fast. Last sentence was meant to be :

"Although here we just look at dddG, we are preparing a follow up manuscript in which we will discuss in detail the effect of every single parameter on ddG and even dG."


On August 20, 2014 10:29:06 PM CEST, Vlad Cojocaru <> wrote:
>In my experience inp=2 gives far better affinities than inp=1 for
>protein-nucleic acids . As long as non-linear PB is used and sasopt=2.
>Therefore I disagree with changing the default to inp=1. In fact I
>would argue MMPBSA should not run with any defaults as users need to
>understand every single parameter.
>For more info, look at the paper by Merino et al which was just
>published in Structure
>Although here we just look at dddG, we are preparing a follow up
>manuscript in which we will discuss in detail the effect of every
>single parameter.
>On August 20, 2014 9:21:13 PM CEST, "Ray Luo, Ph.D." <>
>>I think one reason is that the original inp=2 method was calibrated in
>>reproducing relative affinities due to small changes, i.e. side chain
>>mutations and/or different ligands.
>>If you use it to model absolute binding affinities between proteins
>>and nucleic acids, it breaks down. So neither inp=1 nor inp=2 gives
>>"correct" absolute binding affinities when the "ligands" are also
>>macromolecules. Nevertheless, I still think the relative affinities
>>are better than inp=1 if the relative changes are small. So far, I
>>haven't seen any data on this mailing list that show that the relative
>>affinities by inp=2 are worse than those by inp=1.
>>To address those large ligands, a different calibration has to be
>>developed, i.e. solute scaling now matters and should be taken into
>>account in the model. We are looking into improving the model for the
>>next release.
>>All the best,
>>Ray Luo, Ph.D.
>>Biochemistry, Molecular Biophysics, and
>>Biomedical Engineering
>>University of California, Irvine, CA 92697-3900
>>On Wed, Aug 20, 2014 at 11:34 AM, Jason Swails
>>> On Wed, 2014-08-20 at 11:11 -0700, zahra khatti wrote:
>>>> Dear Amber users
>>>> I obtained positive free energy from
>>> MM/PBSA absolute binding free energies are frequently unreliable.
>>> useful mainly for rank-ordering binding affinities for related
>>>> In my case the receptor and ligand didn't joint together. The
>>distance between them
>>>> is about 1-2 angstrom. Is this related to positive free energy?
>>> Let's have a look:
>>> [snip]
>>>> Differences (Complex - Receptor - Ligand):
>>>> Energy Component Average Std. Dev. Std.
>>Err. of Mean
>>>> VDWAALS -50.0785 1.0295
>> 0.0084
>>>> EEL -1.1552 0.3301
>> 0.0027
>>>> EPB 7.3643 0.8011
>> 0.0065
>>>> ENPOLAR -22.2317 0.3450
>> 0.0028
>>>> EDISPER 354.9084 4.6963
>> 0.0383
>>> Yikes. The EDISPER component of your binding free energy is +350
>>> kcal/mole. Combining that with the repulsive ENPOLAR term, that
>>> your _total_ non-polar solvation free energy contribution to binding
>>> about +330 kcal/mole, which seems outrageous to me.
>>> It seems to me that this is a fairly frequent occurrence with the
>>> "inp=2" non-polar solvation free energy model, so I can't say I
>>> recommend using it. I suggest adding inp=1 to the &pb section of
>>> input file to use the more prototypical, simple SASA-based nonpolar
>>> solvation approximation.
>>> .Developers: Perhaps we should consider either turning the default
>>> to inp=1 or removing the default choice altogether and requiring
>>> to specify it? inp=2 seems to be causing a lot more problems than
>>> solves and gives ludicrous answers more often than inp=1.
>>> All the best,
>>> Jason
>>> --
>>> Jason M. Swails
>>> BioMaPS,
>>> Rutgers University
>>> Postdoctoral Researcher
>>> _______________________________________________
>>> AMBER mailing list
>>AMBER mailing list
>Sent from my Android device with K-9 Mail. Please excuse my brevity.

Sent from my Android device with K-9 Mail. Please excuse my brevity.
AMBER mailing list
Received on Wed Aug 20 2014 - 14:00:03 PDT
Custom Search