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<div class="moz-cite-prefix">Hi,<br>
<br>
I fully understand your sentiments.<br>
But I think this solution, although fine for personal use, it to
ad-hoc to include in Gromacs. Currently the couple-moltype
decouples a whole molecule, which is a very clear operation
(although already somewhat complicated to understand due to all
the different coupling mechanisms). I certainly don't want to
replace this by a index group option. Adding an index group option
is also messy.<br>
<br>
I looked at the domain decomposition code and there is nothing
molecule specific to how the bonded interactions are assigned. So
on the mdrun level there is nothing that prevents the working of
inter-molecular interactions. The only thing that needs to be done
is adding something like an [ intermolecular-interactions ]
section to the topology file processing and the topology data
structure. Having the current processing code go through this is a
matter of adding a few lines. I estimate that implementing this
would take me an hour or so, if we stick to simple, absolute
system (not molecule) atom indices in this section. I can do this
within a week, promise :) The only disadvantage is that the ligand
will not automatically end up in the same periodic image as the
protein.<br>
<br>
I will discuss this with our local developers to get some
feedback.<br>
<br>
Cheers,<br>
<br>
Berk<br>
<br>
On 08/19/2013 08:31 PM, David Mobley wrote:<br>
</div>
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cite="mid:CAPCBi1_16k692Wc7FR=M5QshX2iFcYFrv8UC8XN_fvJtzm0emA@mail.gmail.com"
type="cite">
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<div dir="ltr">Hi, Berk,<br>
<div class="gmail_quote">
<div dir="ltr">
<div>
<div>
<div><br>
</div>
I agree that this solution would be the "proper" one and
would be nice. However, it's been a long time coming
(this is an issue I've been raising for approximately 5
years, and there's no progress; normally no one even
answers). Currently, for the restraints I need to use, I
*have* to merge the ligand into my protein topology,
inconvenient or not. Doing this also means there are
some features I simply can't use (couple-moltype for
example). <br>
<br>
It strikes me that Floris's solution is a good interim
one, in that it at least solves most of the typical use
cases we're facing, and has the advantage of being
*already implemented*. <br>
<br>
</div>
Is there any way we could get this into the main GROMACS,
at least until someone gets time to implementing the
"proper" solution (which could be years from now)?<br>
<br>
</div>
Thanks!<span class="HOEnZb"><font color="#888888"><br>
David<br>
<br>
</font></span></div>
<div class="gmail_extra">
<div>
<div class="h5"><br>
<br>
<div class="gmail_quote">
On Mon, Aug 19, 2013 at 1:10 AM, Berk Hess <span
dir="ltr"><<a moz-do-not-send="true"
href="mailto:hess@kth.se" target="_blank">hess@kth.se</a>></span>
wrote:<br>
<blockquote class="gmail_quote" style="margin:0 0 0
.8ex;border-left:1px #ccc solid;padding-left:1ex">Hi,<br>
<br>
I fully understood this point, maybe my reply wasn't
well structured.<br>
I was trying to argue that the proper solution would
be to implement inter-molecular restraints, instead
of introducing an option which could me misused.
Also merging a ligand topology into your protein
topology is very inconvenient. This problem with the
proper solution is, of course, that someone will
need to implement inter-molecular
restraints/potentials.<br>
<br>
One issue used to be that we corrected molecules for
PBC before calculating bonded interactions. But in
4.6 this is usually not faster and not used any
more. That makes it easier to treat intra- and
inter-molecular interactions the same way at the
mdrun level.<br>
<br>
Cheers,<br>
<br>
Berk
<div>
<div><br>
<br>
On 08/19/2013 09:55 AM, Floris Buelens wrote:<br>
<blockquote class="gmail_quote" style="margin:0
0 0 .8ex;border-left:1px #ccc
solid;padding-left:1ex">
Hi Berk,<br>
<br>
I think some clarification is needed. What
we're talking about is only relevant in the
context of non-bonded interactions, typically
between a small molecule and a protein. To
access the binding affinity of a ligand
through alchemical methods, it's useful to
switch off only the interactions of the ligand
with its environment while maintaining
intra-ligand potentials - this is what's
provided by the 'couple-moltype' code path.<br>
<br>
The limitation that we're trying to circumvent
comes from the fact that as you scale down
interactions with the environment, the ligand
is no longer held in the binding site. To
counteract this, it's necessary to perturb in
restraining potentials as the intramolecular
nonbonded interactions are perturbed out. The
most practical method makes use of a single
distance restraint, two angle and three
dihedral restraints, whose effect can later be
accounted for analytically.<br>
<br>
The current code only allows decoupling of a
whole logical 'molecule' as specified in the
topology file. This precludes the use of
regular (fully perturbation-aware) bonded
interactions. As far as I'm aware, the pull
code doesn't provide what's required.
Inter-molecular bonded interactions would be a
great general solution but presumably won't
show up any time soon.<br>
<br>
The workaround here is instead to represent
two physical molecules (e.g. protein and
ligand) as a single logical molecule (in the
topology file), so regular bonded potentials
can be applied. Current Gromacs doesn't allow
the decoupling ('couple-moltype') code to be
used in this scenario. My modification allows
you to target the ligand by its residue name
and get this functionality back.<br>
<br>
Decoupling a single residue of a multi-residue
chain is indeed probably not correct in this
framework (I did call it 'weird' in my last
message :-) ). An extra check would block
users from trying this.<br>
<br>
I hope that clarifies the problem we're trying
to solve. I agree this will be useful a
relatively small number of users, but on the
other hand it's a very unobtrusive,
self-contained modification which can maintain
full backwards compatibility.<br>
<br>
thanks,<br>
<br>
Floris<br>
<br>
<br>
----- Original Message -----<br>
From: Berk Hess <<a moz-do-not-send="true"
href="mailto:hess@kth.se" target="_blank">hess@kth.se</a>><br>
To: Floris Buelens <<a
moz-do-not-send="true"
href="mailto:floris_buelens@yahoo.com"
target="_blank">floris_buelens@yahoo.com</a>>;
Discussion list for GROMACS development <<a
moz-do-not-send="true"
href="mailto:gmx-developers@gromacs.org"
target="_blank">gmx-developers@gromacs.org</a>><br>
Cc:<br>
Sent: Monday, 19 August 2013, 9:03<br>
Subject: Re: [gmx-developers] free energy
calculations with restraints<br>
<br>
Hi,<br>
<br>
There is the rotational pull code, but that
might not provide the exact<br>
functionality you want.<br>
Already for some time we have been discussing
inter-molecular<br>
interactions, by specifying molecule type,
molecule index and atom<br>
index, but there are no concrete plans for
implementing this yet.<br>
<br>
An option for decoupling part of a molecule
indeed sound useful. But in<br>
practice you always need to replace that part
by something else, at<br>
least a hydrogen, and modify some potentials
of connecting atoms, so I<br>
don't know how generally useful such an option
is.<br>
<br>
Cheers,<br>
<br>
Berk<br>
<br>
On 08/19/2013 07:56 AM, Floris Buelens wrote:<br>
<blockquote class="gmail_quote"
style="margin:0 0 0 .8ex;border-left:1px
#ccc solid;padding-left:1ex">
I suppose that would make sense. The changes
are fairly minor (more or less just the
function convert_moltype_couple and the four
functions it calls) and mainly consist of a
bit of extra juggling with nonbonded
exclusions during preprocessing. The current
functionality (decouple a whole molecule)
could be handled as a special case of the
new code. A check for bonds to the rest of
the structure could stop people from trying
weird stuff like decoupling residues from a
chain.<br>
<br>
<br>
<br>
<br>
________________________________<br>
From: David Mobley <<a
moz-do-not-send="true"
href="mailto:dmobley@gmail.com"
target="_blank">dmobley@gmail.com</a>><br>
To: Floris Buelens <<a
moz-do-not-send="true"
href="mailto:floris_buelens@yahoo.com"
target="_blank">floris_buelens@yahoo.com</a>><br>
Cc: Discussion list for GROMACS development
<<a moz-do-not-send="true"
href="mailto:gmx-developers@gromacs.org"
target="_blank">gmx-developers@gromacs.org</a>><br>
Sent: Friday, 16 August 2013, 18:30<br>
Subject: Re: [gmx-developers] free energy
calculations with restraints<br>
<br>
<br>
<br>
This does sound useful, though it would be
more useful if this could be implemented
into the main GROMACS rather than a separate
code (since otherwise it will go away as
GROMACS is further developed).<br>
<br>
Would this be a possibility going forward,
devels?<br>
<br>
Thanks!<br>
<br>
<br>
<br>
<br>
On Fri, Aug 16, 2013 at 3:07 AM, Floris
Buelens <<a moz-do-not-send="true"
href="mailto:floris_buelens@yahoo.com"
target="_blank">floris_buelens@yahoo.com</a>>
wrote:<br>
<br>
Hi David,<br>
<blockquote class="gmail_quote"
style="margin:0 0 0 .8ex;border-left:1px
#ccc solid;padding-left:1ex">
I have the same requirement as you, but
I've gone about it slightly differently.
I've hacked the couple-moltype code path
to allow decoupling of a specific residue
(identified by name) instead of a
molecule. This allows the residue of
interest to be part of another molecule
block so you can set up distance, angle
and dihedral restraints using regular
bonded interactions with full perturbation
support.<br>
<br>
If this is useful to you or to anyone
else, let me know and I'll be happy to
share.<br>
<br>
best,<br>
<br>
Floris<br>
<br>
________________________________<br>
From: David Mobley <<a
moz-do-not-send="true"
href="mailto:dmobley@gmail.com"
target="_blank">dmobley@gmail.com</a>><br>
<br>
To: Discussion list for GROMACS
development <<a moz-do-not-send="true"
href="mailto:gmx-developers@gromacs.org"
target="_blank">gmx-developers@gromacs.org</a>><br>
Sent: Friday, 14 June 2013, 21:47<br>
Subject: [gmx-developers] free energy
calculations with restraints<br>
<br>
<br>
<br>
<br>
Hi, devs,<br>
<br>
<br>
I'm writing with an issue relating to the
interplay of new free energy features with
restraints.<br>
<br>
I'm very much appreciating some of the new
free energy features in gromacs, such as
the 'couple-moltype' option which provides
a way to set up decoupling or annihilation
of a specific molecule via free energy
calculations without having to edit the
topology file directly. This is especially
great when it comes to decoupling --
charge decoupling was not previously
possible via topology file editing, and
vdW decoupling took substantial
manipulation of the topology file.<br>
<br>
However, for binding free energies, my
work employs orientational restraints
between the protein and ligand. I need to
be able to impose both dihedral and angle
restraints on angles between the protein
and ligand. Currently, I do this using
angle-restraints and dihedral-restraints.
This requires that both the protein and
ligand be within the same logical
'molecule', which (unfortunately) means
that I can't make use of the new free
energy features above, since
couple-moltype has to apply to a whole
molecule, not just part of a molecule.<br>
<br>
So, my I see two possible solutions to the
problem, and hence have these questions:<br>
1) Can dihedral and angle restraints be
applied via the pull code? If not, are
there any plans to add that?<br>
2) Alternatively, what about modifying the
restraints code so it uses (or at least
optionally allows) absolute atom
numbering, rather than numbering within a
specific molecule, thus allowing
restraints (angle-restraints and
dihedral-restraints) to be applied between
'molecules'?<br>
<br>
Thanks!<br>
David<br>
<br>
<br>
<br>
--<br>
David Mobley<br>
<a moz-do-not-send="true"
href="mailto:dmobley@gmail.com"
target="_blank">dmobley@gmail.com</a><br>
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<br>
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<div class="im">-- <br>
<div dir="ltr">David Mobley
<div>Assistant Professor</div>
<div>Department of Pharmaceutical Sciences<br>
</div>
<div>Department of Chemistry<br>
</div>
<div>3134B Natural Sciences I</div>
<div>University of California, Irvine</div>
<div>Irvine, CA 92697</div>
<div><a moz-do-not-send="true"
href="mailto:dmobley@uci.edu" target="_blank">dmobley@uci.edu</a></div>
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-- <br>
David Mobley<br>
<a moz-do-not-send="true" href="mailto:dmobley@gmail.com"
target="_blank">dmobley@gmail.com</a><br>
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