Re: [AMBER] MMPBSA doubt

From: Mary Varughese <>
Date: Thu, 12 May 2016 09:56:46 +0530


I am attaching herewith the output i got from single trajectory approach:
Here deltaG(= -15.91-(-22.43=6.52 a +ve value). As you could see especially
entropy varies much. Taking an average value does'nt seem to be ideal.

And i need to clear one thing about multiple trajectory.
step 1: run three long separate trajectories say a 50 ns each.
step 2:................
          doubt : usually in single trajectory approach if we create say 3

                       rec1: lig1: cmplx1==> deltaPB1 and TdeltaS1
                       rec2: lig2: cmplx2==> deltaPB2 and TdeltaS2
                       rec3: lig3: cmplx3==> deltaPB3 and TdeltaS3

PB total= average(PB1,PB2,PB3); TdeltaS total= average(TS1,TS2,TS3);There
is a correspondence between rec, lig and cmplx

In multiple trajectories there is nothing, I may never get a
I must be missing something in the way doing multiple trajectory approach.
It should be like Find the energy of rec, lig and cmplx for each
trajectory(for the full length of simulation) separately and then find the
difference at the end only. Isnt?
I really dont understand the logic in there.

I feel the ligand do bind favorably (experimentally also) but i am not
getting a favorable value because the flexible chain of the ligand is
moving too much resulting in the varying TdeltaS.

Should i run a long multiple trajectory and do the calculation again.?

Thanking you for the replies

On Wed, May 11, 2016 at 5:55 PM, Jason Swails <>

> On Wed, May 11, 2016 at 7:28 AM, Mary Varughese <>
> wrote:
> > sir
> >
> > I mean it needs long time to converge and has to run separate
> trajectories.
> > is it possible to finalize the calculation with 20 or 30 ns?
> > i tried a 10 ns separate trajectory method as well as 15ns single
> > trajectory. it fails.
> > The ligand do bind throughout the simulation time but delta PB and
> TdeltaS
> > as seen in MMPBSA calculation varies significantly especially TdeltaS
> > varies from negative to positive values. (average of such varying values
> is
> > not reliable isnt?)
> >
> > The ligand is very much flexible with CH3-CH3-CH3 chain. The ligand in
> > individual structure is different from bound structure.
> >
> ​Just because single trajectory MM/PBSA calculations have less variability
> in the binding results does not mean that it is more converged than the
> multiple trajectory approach. Single trajectory analyses are *perfectly*
> correlated -- the bound and unbound conformations are exactly identical.
> As a result, the variability of the binding energies is, by definition, at
> a minimum. But this correlation does not exist in real life -- bound and
> unbound conformations are never identical.
> Naturally once you move to a multiple trajectory approach, the binding
> energies will be a lot more variable and you won't get the illusion of a
> converged simulation. There are other approaches to compute free energies
> of binding based on MD, but none will be cheaper or easier than simply
> running longer simulations for MM/PBSA. You will encounter the same
> sampling problem with any method you choose. If you're encountering
> accuracy problems, you can try a more rigorous method (like thermodynamic
> integration or umbrella sampling/steered MD), but those will be a *lot*
> slower.
> HTH,
> Jason
> --
> Jason M. Swails
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Received on Wed May 11 2016 - 21:30:04 PDT
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