Re: [AMBER] positive free energy

From: Ray Luo, Ph.D. <ray.luo.uci.edu> Date: Wed, 20 Aug 2014 11:59:23 -0700

--
Ray Luo, Ph.D.
Professor,
Biochemistry, Molecular Biophysics, and
Biomedical Engineering
University of California, Irvine, CA 92697-3900
On Wed, Aug 20, 2014 at 11:34 AM, Jason Swails <jason.swails.gmail.com> wrote:
> On Wed, 2014-08-20 at 11:11 -0700, zahra khatti wrote:
>> Dear Amber users
>>
>> I obtained positive free energy from mmpbsa.py.
>
> MM/PBSA absolute binding free energies are frequently unreliable.  It is
> useful mainly for rank-ordering binding affinities for related systems.
>
>> 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 means
> your _total_ non-polar solvation free energy contribution to binding is
> 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 your
> input file to use the more prototypical, simple SASA-based nonpolar
> solvation approximation.
>
> .Developers: Perhaps we should consider either turning the default back
> to inp=1 or removing the default choice altogether and requiring users
> to specify it?  inp=2 seems to be causing a lot more problems than it
> solves and gives ludicrous answers more often than inp=1.
>
> All the best,
> Jason
>
> --
> Jason M. Swails
> BioMaPS,
> Rutgers University
> Postdoctoral Researcher
>
>
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