[gmx-developers] free energy calculations with restraints

David Mobley dmobley at gmail.com
Fri Feb 7 21:58:43 CET 2014


Hi, all,

I'm working on testing this, but have run into an apparent bug in 4.6.x and
this version unearthed by my test system (
http://redmine.gromacs.org/issues/1433). So, I'm temporarily stalled, but
will proceed as soon as it's resolved.

Thanks!



On Wed, Feb 5, 2014 at 1:15 PM, David Mobley <dmobley at gmail.com> wrote:

> For the record, I am currently working on testing this functionality and
> will update as soon as I have news.
>
> Thanks.
>
>
>
> On Fri, Jan 10, 2014 at 6:43 AM, Erik Lindahl <erik.lindahl at scilifelab.se>wrote:
>
>> Hi,
>>
>> In practice I think it's pretty easy: We're unlikely to include this
>> patch in Gromacs-5.0 unless somebody has volunteered and tested that it
>> works correctly ;-)
>>
>> Cheers,
>>
>> Erik
>>
>>
>>
>> On 09 Jan 2014, at 23:11, David Mobley <dmobley at gmail.com> wrote:
>>
>>   Hi, Mark,
>>
>>  I do want to test this soon (it's still on my "soon" list), but
>> realistically it will be at least next week before I can look at it. I'll
>> have a student try and see what she can do as well.
>>
>>  To give a bit of backdrop as to why this is involved/slow -- we use this
>> for doing absolute binding free energy calculations. In the last 8 years or
>> so, we've basically applied these calculations in a total of four different
>> systems. So, while we've wanted this for years (probably, 8+ years!) our
>> throughput is not very high here. Additionally, the calculations are fairly
>> computationally demanding, so we can't just swap in a new set of restraints
>> and have immediate feedback on whether they are working well. We have not
>> set up any NEW absolute free energy calculations since this has been
>> implemented, hence the delay in testing.
>>
>> Realistically, I can have feedback in the next couple weeks on whether it
>> appears to have the features we need, but in terms of whether it is working
>> properly, it would take us much longer (i.e., we would validate absolute
>> binding free energy calculations done with these restraints, versus what we
>> get with the "old" restraints). Perhaps someone else is able to test
>> whether it correctly implements what is supposed to be implemented?
>>
>>  Thanks!
>> David
>>
>>
>>
>>
>> On Wed, Jan 8, 2014 at 10:20 PM, Mark Abraham <mark.j.abraham at gmail.com>wrote:
>>
>>> Hi,
>>>
>>>  Can those who were keen on this feature (David Mobley? Michael
>>> Shirts?) for intermolecular bonded interactions please test it? It's pretty
>>> discouraging to have people claim they've wanted something for years and
>>> then have four months pass without feedback on whether Berk's effort does
>>> what they really want! Please see https://gerrit.gromacs.org/#/c/2566/
>>>
>>>  Thanks,
>>>
>>>  Mark
>>>
>>>
>>> On Mon, Sep 23, 2013 at 1:10 AM, Mark Abraham <mark.j.abraham at gmail.com>wrote:
>>>
>>>> Please can those who have been keen on the feature for which Berk
>>>> kindly wrote some code let us know whether they plan to test it some
>>>> time soon?
>>>>
>>>> Mark
>>>>
>>>> On Sun, Sep 1, 2013 at 5:51 AM, Shirts, Michael (mrs5pt)
>>>>  <mrs5pt at eservices.virginia.edu> wrote:
>>>> > Great, this is exactly the documentation needed to test it.
>>>> >
>>>> > So if one wants to use these as free energy-dependent restraining
>>>> terms,
>>>> > which correspond to the restraint part of the lambda vector, not the
>>>> bonded
>>>> > part, then one just needs to make sure that one uses the restraint
>>>> bonded
>>>> > types, not normal bonded types.
>>>> >
>>>> > I do not there are no explicit angle restraint terms for three atoms.
>>>>  Can
>>>> > the four-atom angle_restraint be used as a three angle restraint by
>>>> > repeating one of the pairs?
>>>> >
>>>> > Best,
>>>> > ~~~~~~~~~~~~
>>>> > Michael Shirts
>>>> > Assistant Professor
>>>> > Department of Chemical Engineering
>>>> > University of Virginia
>>>> > michael.shirts at virginia.edu
>>>> > (434)-243-1821
>>>> >
>>>> >
>>>> >> From: Berk Hess <hess at kth.se>
>>>> >> Date: Sat, 31 Aug 2013 09:31:32 +0200
>>>> >> To: "michael.shirts at virginia.edu" <michael.shirts at virginia.edu>,
>>>> Discussion
>>>> >> list for GROMACS development <gmx-developers at gromacs.org>
>>>> >> Subject: Re: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>
>>>> >> Hi,
>>>> >>
>>>> >> I haven't documented it yet, as I want to be sure this is the
>>>> >> functionality people were asking for.
>>>> >> I didn't add new interaction types, as we can reuse all the grompp
>>>> and
>>>> >> mdrun code and we don't need even more interaction types and requests
>>>> >> for support. At the mdrun level there is no difference between the
>>>> usual
>>>> >> intramolecular and the new intermolecular interactions, except for
>>>> the
>>>> >> graph code, as that only ensure intramolecular interactions don't
>>>> need
>>>> >> pbc treatment.
>>>> >> It is really simple, here is a small example .top file:
>>>> >>
>>>> >> ....
>>>> >>
>>>> >> [ system ]
>>>> >> protein+ligand+water
>>>> >>
>>>> >> [ molecules ]
>>>> >> protein 1 ; 2000 atoms, nr 1-2000
>>>> >> ligand 1 ; 10 atoms, nr 2001-2010
>>>> >> water 10000
>>>> >>
>>>> >> [ intermolecular-interactions ]
>>>> >> ; any bonded type(s) using 2 atoms or more which is a potential
>>>> (e.g. no
>>>> >> vsite, constraints) and does not generate exclusions can follow
>>>> >>
>>>> >> [ angles ]
>>>> >> 803 804 2002 1   30.0 100.0 ; angle potential between 2 protein atoms
>>>> >> and 1 ligand atom
>>>> >>
>>>> >> ...
>>>> >>
>>>> >> Cheers,
>>>> >>
>>>> >> Berk
>>>> >>
>>>> >> On 08/30/2013 11:51 PM, Shirts, Michael (mrs5pt) wrote:
>>>> >>> Berk, just following up on the requests below to make it easier to
>>>> test the
>>>> >>> code:
>>>> >>>
>>>> >>> Thanks!
>>>> >>> ~~~~~~~~~~~~
>>>> >>> Michael Shirts
>>>> >>> Assistant Professor
>>>> >>> Department of Chemical Engineering
>>>> >>> University of Virginia
>>>> >>> michael.shirts at virginia.edu
>>>> >>> (434)-243-1821
>>>> >>>
>>>> >>>
>>>> >>>> From: "Michael R. Shirts" <mrs5pt at eservices.virginia.edu>
>>>> >>>> Reply-To: <michael.shirts at virginia.edu>
>>>> >>>> Date: Wed, 21 Aug 2013 10:09:55 -0400
>>>> >>>> To: Discussion list for GROMACS development <
>>>> gmx-developers at gromacs.org>
>>>> >>>> Subject: Re: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>>>
>>>> >>>> Hi, Berk-
>>>> >>>>
>>>> >>>> * Would it be possible to post (perhaps to redmine?) some example
>>>> files of
>>>> >>>> calling usage?
>>>> >>>>
>>>> >>>> * Perhaps you can provide a bit more of the logic for how this is
>>>> >>>> implemented? I was expecting a new interaction_function type, but
>>>> this seems
>>>> >>>> to be done somewhat differently, and I'm not quite sure how it
>>>> works -- I
>>>> >>>> suspect other people will be confused as well.
>>>> >>>>
>>>> >>>> Best,
>>>> >>>> ~~~~~~~~~~~~
>>>> >>>> Michael Shirts
>>>> >>>> Assistant Professor
>>>> >>>> Department of Chemical Engineering
>>>> >>>> University of Virginia
>>>> >>>> michael.shirts at virginia.edu
>>>> >>>> (434)-243-1821
>>>> >>>>
>>>> >>>>
>>>> >>>>> From: Berk Hess <hess at kth.se>
>>>> >>>>> Reply-To: Discussion list for GROMACS development
>>>> >>>>> <gmx-developers at gromacs.org>
>>>> >>>>> Date: Wed, 21 Aug 2013 17:47:42 +0200
>>>> >>>>> To: Discussion list for GROMACS development <
>>>> gmx-developers at gromacs.org>
>>>> >>>>> Subject: Re: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>>>>
>>>> >>>>> Hi,
>>>> >>>>>
>>>> >>>>> I pushed up a patch to gerrit (master) which is complete afaik,
>>>> but with
>>>> >>>>> a change as extensive as this, there is always a chance I
>>>> overlooked
>>>> >>>>> something:
>>>> >>>>> https://gerrit.gromacs.org/#/c/2566/
>>>> >>>>>
>>>> >>>>> Please try and report back!
>>>> >>>>>
>>>> >>>>> Cheers,
>>>> >>>>>
>>>> >>>>> Berk
>>>> >>>>>
>>>> >>>>> On 08/21/2013 10:08 AM, Mark Abraham wrote:
>>>> >>>>>> Hi,
>>>> >>>>>>
>>>> >>>>>> I've been following with interest, and Berk and I discussed these
>>>> >>>>>> issues yesterday. I'd been afraid there would be artifacts of
>>>> >>>>>> "[moleculetype] is self-contained and exclusive" all through the
>>>> code,
>>>> >>>>>> but Berk seems pretty sure that's not the case. The kind of
>>>> >>>>>> [intermolecule-interactions] suggested above sounds great to me,
>>>> as a
>>>> >>>>>> potential building block for all sorts of things.
>>>> >>>>>>
>>>> >>>>>> Mark
>>>> >>>>>>
>>>> >>>>>> On Tue, Aug 20, 2013 at 7:12 PM, David Mobley <dmobley at gmail.com>
>>>> wrote:
>>>> >>>>>>> Yes, I'm very enthusiastic about adding defined intermolecular
>>>> restraints
>>>> >>>>>>> using absolute atom indices. It seems like a straightforward,
>>>> correct,
>>>> >>>>>>> easy-to-understand way to deal with this simple problem.
>>>> >>>>>>>
>>>> >>>>>>> David
>>>> >>>>>>>
>>>> >>>>>>>
>>>> >>>>>>>
>>>> >>>>>>> On Tue, Aug 20, 2013 at 9:39 AM, Shirts, Michael (mrs5pt)
>>>> >>>>>>> <mrs5pt at eservices.virginia.edu> wrote:
>>>> >>>>>>>> The other thing I would say is that the couple-mol code is a
>>>> little
>>>> >>>>>>>> difficult to work with----there's known quirks, like handling
>>>> the
>>>> >>>>>>>> intramolecular dispersion in a way that's slightly off from
>>>> free energy
>>>> >>>>>>>> off,
>>>> >>>>>>>> as well as some new quirks that I'll try to post about later
>>>> this
>>>> >>>>>>>> week---that it would actually be cleaner to add clearly defined
>>>> >>>>>>>> intermolecular restraints than add complexity to the coupling
>>>> feature.
>>>> >>>>>>>>
>>>> >>>>>>>> Best,
>>>> >>>>>>>> ~~~~~~~~~~~~
>>>> >>>>>>>> Michael Shirts
>>>> >>>>>>>> Assistant Professor
>>>> >>>>>>>> Department of Chemical Engineering
>>>> >>>>>>>> University of Virginia
>>>> >>>>>>>> michael.shirts at virginia.edu
>>>> >>>>>>>> (434)-243-1821
>>>> >>>>>>>>
>>>> >>>>>>>>
>>>> >>>>>>>>> From: Floris Buelens <floris_buelens at yahoo.com>
>>>> >>>>>>>>> Reply-To: Floris Buelens <floris_buelens at yahoo.com>,
>>>> Discussion list
>>>> >>>>>>>>> for
>>>> >>>>>>>>> GROMACS development <gmx-developers at gromacs.org>
>>>> >>>>>>>>> Date: Tue, 20 Aug 2013 08:35:15 -0400
>>>> >>>>>>>>> To: Berk Hess <hess at kth.se>, Discussion list for GROMACS
>>>> development
>>>> >>>>>>>>> <gmx-developers at gromacs.org>
>>>> >>>>>>>>> Subject: Re: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>>>>>>>>
>>>> >>>>>>>>> Hi Berk,
>>>> >>>>>>>>>
>>>> >>>>>>>>> I think we might have gone out of sync there - I sent the
>>>> message below
>>>> >>>>>>>>> before
>>>> >>>>>>>>> reading yours from this morning. From the misplaced context
>>>> it maybe
>>>> >>>>>>>>> sounded
>>>> >>>>>>>>> like I was disagreeing with your '[
>>>> intermolecular-interactions ]'
>>>> >>>>>>>>> suggestion,
>>>> >>>>>>>>> which I'm definitely not - this would clearly be preferable
>>>> and
>>>> >>>>>>>>> probably
>>>> >>>>>>>>> useful to a wider audience.
>>>> >>>>>>>>>
>>>> >>>>>>>>>
>>>> >>>>>>>>>
>>>> >>>>>>>>> ----- Original Message -----
>>>> >>>>>>>>> From: Berk Hess <hess at kth.se>
>>>> >>>>>>>>> To: Floris Buelens <floris_buelens at yahoo.com>; Discussion
>>>> list for
>>>> >>>>>>>>> GROMACS
>>>> >>>>>>>>> development <gmx-developers at gromacs.org>
>>>> >>>>>>>>> Cc:
>>>> >>>>>>>>> Sent: Tuesday, 20 August 2013, 12:04
>>>> >>>>>>>>> Subject: Re: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>>>>>>>>
>>>> >>>>>>>>> Hi,
>>>> >>>>>>>>>
>>>> >>>>>>>>> We could consider this.
>>>> >>>>>>>>> I don't know how you did this now, but this would need an
>>>> extra mdp
>>>> >>>>>>>>> option, something like couple-group, to avoid one option with
>>>> a moltype
>>>> >>>>>>>>> or index group as an input.
>>>> >>>>>>>>> Then we would also need to decide what to do with a group
>>>> which is part
>>>> >>>>>>>>> of one molecule of a certain moleculetype with multiple
>>>> copies.
>>>> >>>>>>>>> Disallow
>>>> >>>>>>>>> this? Or duplicate the moltype and only modify one copy (as
>>>> is done now
>>>> >>>>>>>>> for qmmm)?
>>>> >>>>>>>>>
>>>> >>>>>>>>> Cheers,
>>>> >>>>>>>>>
>>>> >>>>>>>>> Berk
>>>> >>>>>>>>>
>>>> >>>>>>>>> On 08/20/2013 09:24 AM, Floris Buelens wrote:
>>>> >>>>>>>>>> Hi,
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> I would also still argue for augmenting the current
>>>> couple-moltype
>>>> >>>>>>>>>> functionality with this modification. I can see this is a
>>>> niche
>>>> >>>>>>>>>> requirement,
>>>> >>>>>>>>>> which of course does speak against inclusion. But in my view
>>>> the
>>>> >>>>>>>>>> replacement
>>>> >>>>>>>>>> code is no less elegant than the current implementation
>>>> (modification
>>>> >>>>>>>>>> of five
>>>> >>>>>>>>>> self-contained functions at the pre-processing stage, maybe
>>>> 50-odd
>>>> >>>>>>>>>> extra
>>>> >>>>>>>>>> lines), we can maintain full backward compatibility, and a
>>>> single
>>>> >>>>>>>>>> simple
>>>> >>>>>>>>>> check will remove any potential for accidental misuse.
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> ________________________________
>>>> >>>>>>>>>> From: David Mobley <dmobley at uci.edu>
>>>> >>>>>>>>>> To: Discussion list for GROMACS development
>>>> >>>>>>>>>> <gmx-developers at gromacs.org>
>>>> >>>>>>>>>> Cc: Floris Buelens <floris_buelens at yahoo.com>; Michael R.
>>>> Shirts
>>>> >>>>>>>>>> <michael.shirts at virginia.edu>
>>>> >>>>>>>>>> Sent: Monday, 19 August 2013, 20:02
>>>> >>>>>>>>>> Subject: Re: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> Hi, Berk,
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> 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).
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> 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*.
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> 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)?
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> Thanks!
>>>> >>>>>>>>>> David
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> On Mon, Aug 19, 2013 at 1:10 AM, Berk Hess <hess at kth.se>
>>>> wrote:
>>>> >>>>>>>>>>
>>>> >>>>>>>>>> Hi,
>>>> >>>>>>>>>>> I fully understood this point, maybe my reply wasn't well
>>>> structured.
>>>> >>>>>>>>>>> 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.
>>>> >>>>>>>>>>>
>>>> >>>>>>>>>>> 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.
>>>> >>>>>>>>>>>
>>>> >>>>>>>>>>> Cheers,
>>>> >>>>>>>>>>>
>>>> >>>>>>>>>>> Berk
>>>> >>>>>>>>>>>
>>>> >>>>>>>>>>>
>>>> >>>>>>>>>>> On 08/19/2013 09:55 AM, Floris Buelens wrote:
>>>> >>>>>>>>>>>
>>>> >>>>>>>>>>> Hi Berk,
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> thanks,
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> Floris
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> ----- Original Message -----
>>>> >>>>>>>>>>>> From: Berk Hess <hess at kth.se>
>>>> >>>>>>>>>>>> To: Floris Buelens <floris_buelens at yahoo.com>; Discussion
>>>> list for
>>>> >>>>>>>>>>>> GROMACS
>>>> >>>>>>>>>>>> development <gmx-developers at gromacs.org>
>>>> >>>>>>>>>>>> Cc:
>>>> >>>>>>>>>>>> Sent: Monday, 19 August 2013, 9:03
>>>> >>>>>>>>>>>> Subject: Re: [gmx-developers] free energy calculations with
>>>> >>>>>>>>>>>> restraints
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> Hi,
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> There is the rotational pull code, but that might not
>>>> provide the
>>>> >>>>>>>>>>>> exact
>>>> >>>>>>>>>>>> functionality you want.
>>>> >>>>>>>>>>>> Already for some time we have been discussing
>>>> inter-molecular
>>>> >>>>>>>>>>>> interactions, by specifying molecule type, molecule index
>>>> and atom
>>>> >>>>>>>>>>>> index, but there are no concrete plans for implementing
>>>> this yet.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> An option for decoupling part of a molecule indeed sound
>>>> useful. But
>>>> >>>>>>>>>>>> in
>>>> >>>>>>>>>>>> practice you always need to replace that part by something
>>>> else, at
>>>> >>>>>>>>>>>> least a hydrogen, and modify some potentials of connecting
>>>> atoms, so
>>>> >>>>>>>>>>>> I
>>>> >>>>>>>>>>>> don't know how generally useful such an option is.
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> Cheers,
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> Berk
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> On 08/19/2013 07:56 AM, Floris Buelens wrote:
>>>> >>>>>>>>>>>>
>>>> >>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> ________________________________
>>>> >>>>>>>>>>>>> From: David Mobley <dmobley at gmail.com>
>>>> >>>>>>>>>>>>> To: Floris Buelens <floris_buelens at yahoo.com>
>>>> >>>>>>>>>>>>> Cc: Discussion list for GROMACS development
>>>> >>>>>>>>>>>>> <gmx-developers at gromacs.org>
>>>> >>>>>>>>>>>>> Sent: Friday, 16 August 2013, 18:30
>>>> >>>>>>>>>>>>> Subject: Re: [gmx-developers] free energy calculations
>>>> with
>>>> >>>>>>>>>>>>> restraints
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> 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).
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> Would this be a possibility going forward, devels?
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> Thanks!
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> On Fri, Aug 16, 2013 at 3:07 AM, Floris Buelens
>>>> >>>>>>>>>>>>> <floris_buelens at yahoo.com>
>>>> >>>>>>>>>>>>> wrote:
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> Hi David,
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>> If this is useful to you or to anyone else, let me know
>>>> and I'll be
>>>> >>>>>>>>>>>>> happy
>>>> >>>>>>>>>>>>> to share.
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> best,
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> Floris
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> ________________________________
>>>> >>>>>>>>>>>>> From: David Mobley <dmobley at gmail.com>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> To: Discussion list for GROMACS development
>>>> >>>>>>>>>>>>> <gmx-developers at gromacs.org>
>>>> >>>>>>>>>>>>> Sent: Friday, 14 June 2013, 21:47
>>>> >>>>>>>>>>>>> Subject: [gmx-developers] free energy calculations with
>>>> restraints
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> Hi, devs,
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> I'm writing with an issue relating to the interplay of
>>>> new free
>>>> >>>>>>>>>>>>> energy
>>>> >>>>>>>>>>>>> features with restraints.
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> 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.
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> So, my I see two possible solutions to the problem, and
>>>> hence have
>>>> >>>>>>>>>>>>> these
>>>> >>>>>>>>>>>>> questions:
>>>> >>>>>>>>>>>>> 1) Can dihedral and angle restraints be applied via the
>>>> pull code?
>>>> >>>>>>>>>>>>> If
>>>> >>>>>>>>>>>>> not, are there any plans to add that?
>>>> >>>>>>>>>>>>> 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'?
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> Thanks!
>>>> >>>>>>>>>>>>> David
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> --
>>>> >>>>>>>>>>>>> David Mobley
>>>> >>>>>>>>>>>>> dmobley at gmail.com
>>>> >>>>>>>>>>>>> 949-385-2436
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>> --
>>>> >>>>>>>>>>>>> gmx-developers mailing list
>>>> >>>>>>>>>>>>> gmx-developers at gromacs.org
>>>> >>>>>>>>>>>>> http://lists.gromacs.org/mailman/listinfo/gmx-developers
>>>> >>>>>>>>>>>>> Please don't post (un)subscribe requests to the list. Use
>>>> the
>>>> >>>>>>>>>>>>> www interface or send it to
>>>> gmx-developers-request at gromacs.org.
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>>>>
>>>> >>>>>>>>>>> --
>>>> >>>>>>>>>>> gmx-developers mailing list
>>>> >>>>>>>>>>> gmx-developers at gromacs.org
>>>> >>>>>>>>>>> http://lists.gromacs.org/mailman/listinfo/gmx-developers
>>>> >>>>>>>>>>> Please don't post (un)subscribe requests to the list. Use
>>>> the www
>>>> >>>>>>>>>>> interface
>>>> >>>>>>>>>>> or send it to gmx-developers-request at gromacs.org.
>>>> >>>>>>>>>>>
>>>> >>>>>>>>> --
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>>>> >>>>>>>>> gmx-developers at gromacs.org
>>>> >>>>>>>>> http://lists.gromacs.org/mailman/listinfo/gmx-developers
>>>> >>>>>>>>> Please don't post (un)subscribe requests to the list. Use the
>>>> >>>>>>>>> www interface or send it to
>>>> gmx-developers-request at gromacs.org.
>>>> >>>>>>>> --
>>>> >>>>>>>> gmx-developers mailing list
>>>> >>>>>>>> gmx-developers at gromacs.org
>>>> >>>>>>>> http://lists.gromacs.org/mailman/listinfo/gmx-developers
>>>> >>>>>>>> Please don't post (un)subscribe requests to the list. Use the
>>>> >>>>>>>> www interface or send it to gmx-developers-request at gromacs.org
>>>> .
>>>> >>>>>>>
>>>> >>>>>>>
>>>> >>>>>>> --
>>>> >>>>>>> David Mobley
>>>> >>>>>>> dmobley at gmail.com
>>>> >>>>>>> 949-385-2436
>>>> >>>>>>>
>>>> >>>>>>> --
>>>> >>>>>>> gmx-developers mailing list
>>>> >>>>>>> gmx-developers at gromacs.org
>>>> >>>>>>> http://lists.gromacs.org/mailman/listinfo/gmx-developers
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>>>> >>>>> --
>>>> >>>>> gmx-developers mailing list
>>>> >>>>> gmx-developers at gromacs.org
>>>> >>>>> http://lists.gromacs.org/mailman/listinfo/gmx-developers
>>>> >>>>> Please don't post (un)subscribe requests to the list. Use the
>>>> >>>>> www interface or send it to gmx-developers-request at gromacs.org.
>>>> >>
>>>> >
>>>> > --
>>>> > gmx-developers mailing list
>>>> > gmx-developers at gromacs.org
>>>> > http://lists.gromacs.org/mailman/listinfo/gmx-developers
>>>> > Please don't post (un)subscribe requests to the list. Use the
>>>> > www interface or send it to gmx-developers-request at gromacs.org.
>>>>
>>>
>>>
>>> --
>>> Gromacs Developers mailing list
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>>
>>
>>
>> --
>> David Mobley
>> dmobley at gmail.com
>> 949-385-2436
>>  --
>> Gromacs Developers mailing list
>>
>> * Please search the archive at
>> http://www.gromacs.org/Support/Mailing_Lists/GMX-developers_List before
>> posting!
>>
>> * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists
>>
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>> gmx-developers-request at gromacs.org.
>>
>>
>>
>> --
>> Gromacs Developers mailing list
>>
>> * Please search the archive at
>> http://www.gromacs.org/Support/Mailing_Lists/GMX-developers_List before
>> posting!
>>
>> * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists
>>
>> * For (un)subscribe requests visit
>> https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-developersor send a mail to
>> gmx-developers-request at gromacs.org.
>>
>
>
>
> --
> David Mobley
> dmobley at gmail.com
> 949-385-2436
>



-- 
David Mobley
dmobley at gmail.com
949-385-2436
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