VMD-L Mailing List

From: Francesco Pietra (chiendarret_at_gmail.com)
Date: Sun Mar 25 2018 - 04:24:50 CDT

In retrospect, I must admit that my question "why 50 lambda windows were
not enough to reach quasi convergence for the Unbound case?" was a silly
question.Reaching quasi convergence is a serious problem.

I have now further tried with the Unbound by increasing both
pre-equilibration and FEP steps, while shortening the number of windows in
order to keep the calculations within the allowed 24hr at the cluster (more
that one node of 36 cores is attended by poorer performance). I got better
results for free energy: red line at -5.5, black line at -10.0. Again, it
could be noticed that the system answers positively to more chances toward
convergence.

In my view, all that shows that present analysis tools do not allow
carrying out FEP simulations with protein-ligand complexes of current real
interest. Chance should be given of carrying out FEP simulations in steps,
say lamda 0.0-0.5 0.5-1.0, or,very likely, even more fractionated. Finally
concatenating the .fepout files. Unless one has unlimited time of execution
at the cluster, which is not my case, but would be risky anyway of easily
loosing everything.

One could object that "organic" ligands pose problems of compatibility with
protein FF. However, I noticed that quasi convergence was reported by
merely parameterizing the organic ligands with GAFF FF at semiempirical
level (Chem. Sci., 2016, 7, 207). I believe that by fitting dihedrals and
water interaction for charmm at HF-6-31G* level, I did better.

I appreciated very much receiving by Brian "You can indeed, under certain
circumstances, just concatenate output from multiple runs, but things must
be in the right format for ParseFEP to detect it. That means you would have
to sort and interleave the data at the same lambda value, probably strip
out some of the comments, and then re-concatenate everything into a single
file."
I am prone to undertake such a job, because the alternative is abandoning
the project for which I received a grant (what never happened to me
before). However, I would need some more detailed instructions, perhaps a
sketch of execution, or what else.

Thanks

francesco

---------- Forwarded message ----------
From: Francesco Pietra <chiendarret_at_gmail.com>
Date: Fri, Mar 23, 2018 at 9:31 PM
Subject: Re: vmd-l: Fwd: ParseFEP for restating FEP
To: Brian Radak <brian.radak_at_gmail.com>
Cc: NAMD <namd-l_at_ks.uiuc.edu>, VMD Mailing List <vmd-l_at_ks.uiuc.edu>

Hi Brian:

(1)

running each lambda as its own NAMD job,
>

As the very reason for that is to have more lambda windows than 24hr of
cluster would allow with a standard execution, that strategy is simple
impossible in the organization of the cluster I have access to. No short
queues.

(2)

concatenate output from multiple runs, but things must be in the right
> format for ParseFEP to detect it.
>

namd has a quite multiform audience, comprising also people that, like
myself, have an experimental formation (biochemistry), while short in
programming (and short of time to learn programming at a level for these
affairs). Could namd consider to devote some time (probably no long time in
the hands of experts) to allow semi-automatic concatenation of ,fepout
outputs from FEP simulations as currently carried out?

(3)

Another, probably much more serious problem, is why 50 lambda windows were
not enough to reach quasi convergence for the Unbound case? The ligand is
not small and quite complex, like diterpenoids are. However, I spent
several weeks in parameterizing it with dihedral and water-interaction
fitting. Both the ligand alone, and the complex with the protein, allow
hundreds of ns of MD without any problem. I am aware that the FEP tutorial
for ligand-protein was for a peptide ligand, declaring the wish to avoid
the problems with "natural products". However, should the latter be not
FEP- workable, a whole area of interest (think to pharmaceutical interests)
would be out.

I hope that namd team will take (2) above into serious consideration,
without having to wait for namd 2.13.

Thanks a lot for all your advice.

francesco

On Fri, Mar 23, 2018 at 4:48 PM, Brian Radak <brian.radak_at_gmail.com> wrote:

> Unfortunately there is not currently an elegant solution for this. You can
> indeed, under certain circumstances, just concatenate output from multiple
> runs, but things must be in the right format for ParseFEP to detect it.
> That means you would have to sort and interleave the data at the same
> lambda value, probably strip out some of the comments, and then
> re-concatenate everything into a single file.
>
> If you are running each lambda as its own NAMD job, then this should not
> be too hard - just "grep -v #" the fepout files after the first one:
>
> Here's a bash example for N jobs (N-1 restarts) and M lambda values --
> I've assumed a specific file naming scheme that should be pretty
> transparent and mappable onto whatever you've done.
>
> rm -f all_lambda.fepout 2> /dev/null
> for ((m=0; m<$M; m++))
> do
> cat lambda${m}_job1.fepout >> all_lambda.fepout
> for ((n=2; n<=$N; n++))
> do
> grep -v "#" lambda${m}_job${n} >> all_lambda.fepout
> done
> done
>
> all_lambda.fepout *should* work in ParseFEP, but I've never actually
> tried something like this.
>
> I know this is not pretty and we're trying to improve things for NAMD
> 2.13, especially with regards to automating parallel runs.
>
> Brian
>
>
>
> On Fri, Mar 23, 2018 at 10:00 AM, Francesco Pietra <chiendarret_at_gmail.com>
> wrote:
>
>> Otherwise, is it possible to run portions of lambda and then concatenate
>> the .fepout results?
>> ---------- Forwarded message ----------
>> From: Francesco Pietra <chiendarret_at_gmail.com>
>> Date: Fri, Mar 23, 2018 at 8:05 AM
>> Subject: ParseFEP for restating FEP
>> To: NAMD <namd-l_at_ks.uiuc.edu>, VMD Mailing List <vmd-l_at_ks.uiuc.edu>
>>
>>
>> Hello:
>> May I ask whether there is any plan to make ParseFEP plugin capable of
>> dealing with restarted FEP.
>>
>> With receptor-ligand, I found it difficult to get matching free energy
>> for frwd/back in the 24hr hr allowed on the cluster, taking into account
>> that I used the max number of nodes for the given size of the system.
>>
>> Thus, for the UNBOUND simulations, with either SOS or BAR estimator,
>> Probability Distribution was found to improve from 1 to 4 until good
>> overlapping, while Free Energy also improves correspondingly, albeit not
>> doing better than red at -2.50, black at -10.0. By restarting until 100
>> windows, probably I should have acceptable convergence. Curiously
>> Enthalpy/Entropy match better (artifact).
>>
>> I used fifty windows with 50,000 pre-equilibration and 300,000 FEP only
>> (1 node), in order to stay within the 24hr. (a smaller number of windows,
>> even with much pre-equilibration and FEP, perform worser).
>> With the ligand-protein I could use a max of 4 nodes (beyond which no
>> higher speed) with perhaps a max of 10 windows. Bad prospects for
>> convergence.
>>
>> Thanks for your attention
>>
>> francesco pietra
>>
>>
>