AMBER Archive (2006)

Subject: Re: AMBER: Question about free energy with mm_pbsa

From: William Wei (william.wei_at_utoronto.ca)
Date: Fri Sep 01 2006 - 08:32:29 CDT

Hi Tom and Dac, Thank you very very much for your informations. It did
helped me a lot to get a feeling for mmpbsa.
Best regards,
William
----- Original Message -----
From: "Thomas Cheatham" <tec3_at_utah.edu>
To: <amber_at_scripps.edu>
Sent: Friday, September 01, 2006 2:23 AM
Subject: Re: AMBER: Question about free energy with mm_pbsa

>
> > Question 1: While we use mm-pbsa for calculating the delta G, both GB
and
> > PB do not minimize the complex, receptor and ligand. The complex
snapshots
> > are at a relatively low energy conformations, but those snapshots of
>
> As dac mentioned, this is a feature; stated another way, if you run
> separate trajectories for each, differential relaxation in each
> (potentially unrelated to the binding) may lead to more noise. For
> example, maybe in the simulation of the complex, some motion in the tail
> unrelated to the binding leads to effectively a lower energy state. If
> this same motion is not sampled in the "free" receptor (in a multiple
> separate trajectory approach), this will tend to overstabilize the
> binding. Even with single trajectory approaches, if you are trying to
> compare multiple different ligands and run a series of different
> ligand-bound complexes, each may differentially "relax". This is
> discussed a little bit in Spackova et al. JACS (2003) in the supplementary
> material and in other MM-PBSA papers and reviews.
>
> > Question 2: In mm-pbsa NM section, if we use the same number of
snapshots
> > as we used for delta E calculation, it will take too long time to finish
the
> > Nmode calculation. For the continuous snapshots, after minimization, I
can
> > imagine that many snapshots would share the same conformation. So is
that
> > okay if we use fewer snapshots for Nmode calculation, let's say 1 in
about
> > 10 snapshots?
>
> Clearly the cost of NMODE calculations on each frame is prohibitive. If
> you look at the early MM-PBSA papers and even more recent, a much smaller
> set of frames are investigated by NMODE, or quasi-harmonic estimates of
> the entropy are applied (for example papers of Laughton and/or Orozco).
> If I were forced to judge the question of how many are necessary, I would
> have to do some statistical analysis and maybe block average comparisons
> for my particular case.
>
> > Question 3: After the simulation system reached equilibrium, how many
> > snapshots we should use for delta G calculation? What is the reasonable
> > period?
>
> I do not intend to sound pessimistic and I will not claim I have all the
> answers here, but the best thing to do is to test and find out. Also, I
> would careful with assumptions that you have reached equilibrium, and more
> importantly, how you judge if you have attained equilibrium. Some
> properties converge very rapidly, others will not converge in 10-100ns
> simulations.
>
> If you look to the literature, "reasonable periods" in common usage range
> from 100 ps in some papers to 10's of ns in others. Longer does not
> necessarilly mean better as differential relaxation in the stochastic MD
> trajectories of various complexes can lead to noise or artifactual
> calculated differences in the estimated energetics.
>
> Remember that these energetic estimates are only one tool in the arsenal
> for attempting to understand what is happening in a simulation. Also note
> that in addition to the MM-PBSA papers by many groups, consider looking at
> related methods that look at averages over trajectories, such as the ES/IS
> methods of Hermans, linear interaction energy approaches of Aqvist, etc.
>
> --tom
>
> -----------------------------------------------------------------------
> The AMBER Mail Reflector
> To post, send mail to amber_at_scripps.edu
> To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu
>

-----------------------------------------------------------------------
The AMBER Mail Reflector
To post, send mail to amber_at_scripps.edu
To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu