[gmx-users] Performing energy minimisation for an alanine scan
Anthony Nash
anthony.nash at dpag.ox.ac.uk
Mon Jul 9 15:12:47 CEST 2018
Thanks for your help. I completely agree with your points raised. I've dropped the pmx developers and email, hopefully there will be a little bit of wiggle room for me to move forward on this project some time soon.
Thanks again, and to Mark and Justin.
Anthony
Kind regards
Anthony Nash PhD MRSC
Department of Physiology, Anatomy, and Genetics
University of Oxford
________________________________
From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Abhishek Acharya <abhi117acharya at gmail.com>
Sent: 09 July 2018 13:47:57
To: Discussion list for GROMACS users
Subject: Re: [gmx-users] Performing energy minimisation for an alanine scan
I see your problem. Automating pdb2gmx should be easy if one blindly
accepts the protonation states assigned. It does work for most proteins,
but I have encountered problematic cases. But, if you notice, weven the pmx
web-service seems to use pdb2gmx for generating the topology files. Or
else, it required a structure with protons already added.
My suggestion pertains to the point raised by Mark; it would indeed be nice
to have a utility that can provide both the mutated coordinate as well as
topology file.
So the workflow could be something like this:
1. Generate input coordinate file with protons already added.
2. Use pmx mutate tool to generate the 'mutated' coordinate and topology
files.
3. Rest of the steps...
The first step is where one needs to be careful. The second step should
work with the modified mutres.mtp. Rest can be automated trivially.
If what I suggested in the previous mail doesn't work, then it will require
changes in the pmx code.
Good luck.
Abhishek
On Mon, Jul 9, 2018 at 5:54 PM, Anthony Nash <anthony.nash at dpag.ox.ac.uk>
wrote:
> Thanks Abhishek,
>
>
> I'll have to give this some thought when I have some hours to spare. I
> believe the damage has been done as I already have my 600+ coordinate and
> respective structures as part of the pmx web-service. With their output I
> was able to get stright in there with my editconf, genion, solvate etc.,
> steps immediately with the provided .pdb file.
>
>
> Are you suggesting I run a pdb2gmx over the 600+ .pdb files using a
> modified (as per your emails below) FF? If so I would imagine that would be
> easy enough to automate.
>
>
> Thanks
>
> Anthony
>
>
> Kind regards
> Anthony Nash PhD MRSC
> Department of Physiology, Anatomy, and Genetics
> University of Oxford
> ________________________________
> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Abhishek
> Acharya <abhi117acharya at gmail.com>
> Sent: 09 July 2018 13:19:07
> To: Discussion list for GROMACS users
> Subject: Re: [gmx-users] Performing energy minimisation for an alanine scan
>
> Hello Anthony,
>
> I was just looking at this aspect. In the mutres.mtp file try to replace
> just the [coords] section with this:
>
> [ coords ]
> -2.994 -4.470 6.993
> -3.510 -5.332 7.063
> -1.676 -4.415 7.600
> -1.774 -4.901 8.572
> -0.668 -5.234 6.757
> -1.036 -6.255 6.636
> -0.582 -4.816 5.754
> 0.620 -5.297 7.342
> -1.234 -2.969 7.858
> -1.305 -2.106 6.983
>
> I think, this just might work. I assume you are only interested in
> generating the correct coordinate file. Topology construction can be done
> by pdb2gmx later on.
>
> See if this works.
>
> Abhishek
>
>
>
>
> Abhishek Acharya
> Research Associate,
> Department of Molecular Nutrition
> CSIR-Central Food Technological Research Institute,
> Mysuru-570020
>
> On Mon, Jul 9, 2018 at 5:36 PM, Anthony Nash <anthony.nash at dpag.ox.ac.uk>
> wrote:
>
> > Hello Abhishek,
> >
> >
> > I think you are onto something there. I've just found the mutres.mtp
> file.
> >
> > I can understand the idea of simply changing all [X2A] residue topologies
> > but then how do I reflect these changes in the coordinate files? Sorry,
> > this is probably quite simple, I've just stuck between five projects
> today
> > with little room to think.
> >
> >
> > Thanks
> >
> > Anthony
> >
> >
> > Kind regards
> > Anthony Nash PhD MRSC
> > Department of Physiology, Anatomy, and Genetics
> > University of Oxford
> > ________________________________
> > From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> > gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Abhishek
> > Acharya <abhi117acharya at gmail.com>
> > Sent: 09 July 2018 12:52:01
> > To: Discussion list for GROMACS users
> > Subject: Re: [gmx-users] Performing energy minimisation for an alanine
> scan
> >
> > Hello Anthony,
> >
> > Just out of curiosity, I checked the pmx code. It looks like a simple
> hack
> > into the hybrid residue database (mutres.mtp file, present in the ff
> > directories supplied by the authors) should do the trick. If you look
> into
> > this file, it contains the full topology and coords for all possible aa
> to
> > aa transformations. So, for alanine scanning, I would try to replace all
> > [X2A] sections in mutres.mtp to just ala topology (X=any aa).
> >
> > Hope this helps.
> >
> > Abhishek Acharya
> >
> >
> >
> > On Mon, Jul 9, 2018 at 3:15 AM, Anthony Nash <anthony.nash at dpag.ox.ac.uk
> >
> > wrote:
> >
> > > Thanks Mark, sounds like a good idea.
> > >
> > >
> > > Kind regards
> > > Anthony Nash PhD MRSC
> > > Department of Physiology, Anatomy, and Genetics
> > > University of Oxford
> > > ________________________________
> > > From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> > > gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Mark
> > > Abraham <mark.j.abraham at gmail.com>
> > > Sent: 08 July 2018 22:38:41
> > > To: gmx-users at gromacs.org
> > > Subject: Re: [gmx-users] Performing energy minimisation for an alanine
> > scan
> > >
> > > Hi,
> > >
> > > The log and energy output reports the lambda value. And of course you
> can
> > > compare the value from a single point energy from a single-topology
> > > equivalent coordinate input.
> > >
> > > Mark
> > >
> > > On Sun, Jul 8, 2018 at 10:17 PM Anthony Nash <
> anthony.nash at dpag.ox.ac.uk
> > >
> > > wrote:
> > >
> > > > Hi Justin and Mark,
> > > >
> > > >
> > > > Thank you for your replies. Very helpful indeed.
> > > >
> > > > In answer to Justin's question, yes, I simply used the Free Energy
> .mdp
> > > > options as a hack to get the structure into state B. This was a
> > shortcut
> > > to
> > > > the horror which would have been opening 600+ structures in something
> > > like
> > > > Maestro and make the change by hand.
> > > >
> > > >
> > > > As a point of validation, besides blind faith in Gromacs, what is
> there
> > > > that I can do to ensure stateB was used? I have noticed a warning:
> > > >
> > > >
> > > > "Some parameters for bonded interaction involving perturbed atoms
> are
> > > > specified explicitly in state A, but not B - copying A to"
> > > >
> > > > This was from aspartic acid(stateA) -> Alanine(stateB), after using
> > .mdp
> > > > options which should have immediately put the structure into stateB.
> > > >
> > > > Mark, that's a good idea. I think it would be an excellent feature of
> > > pmx,
> > > > I'll drop them an email. I am not too concerned by the overall
> > > performance.
> > > > I am only using the lambda endpoint 1. The 600+ simulations that I
> will
> > > be
> > > > performing is to map a drug binding site volume (could also be
> overall
> > > > protein SASA if the entry site closes) as a function of a single
> point
> > > > mutation in the protein sequence. I won't be pushing each structure
> for
> > > > very long after equilibrium.
> > > >
> > > >
> > > > Thanks both
> > > >
> > > > Anthony
> > > >
> > > >
> > > > Kind regards
> > > > Anthony Nash PhD MRSC
> > > > Department of Physiology, Anatomy, and Genetics
> > > > University of Oxford
> > > > ________________________________
> > > > From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> > > > gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Mark
> > > > Abraham <mark.j.abraham at gmail.com>
> > > > Sent: 08 July 2018 19:21:17
> > > > To: gmx-users at gromacs.org
> > > > Subject: Re: [gmx-users] Performing energy minimisation for an
> alanine
> > > scan
> > > >
> > > > Hi,
> > > >
> > > > Justin is definitely right about performance for lambda not 0 or 1,
> but
> > > > pretty much all of the forms of slowness for FE calculations are
> > > trivially
> > > > avoidable for the endpoints. I just don't know that the code does
> that,
> > > and
> > > > I can't check the dozens of places to be sure, so I encourage Anthony
> > to
> > > > compare performance, if he wants to proceed with this approach. As
> > Justin
> > > > suggests, it would certainly be simpler if there was a way to
> generate
> > > the
> > > > coordinates of the mutated state as a single-topology structure. Do
> get
> > > in
> > > > touch with the authors of pmx, though, as if it's not currently
> > possible
> > > it
> > > > sounds to me like a useful feature.
> > > >
> > > > Mark
> > > >
> > > > On Sun, Jul 8, 2018 at 8:12 PM Justin Lemkul <jalemkul at vt.edu>
> wrote:
> > > >
> > > > >
> > > > >
> > > > > On 7/7/18 6:09 PM, Anthony Nash wrote:
> > > > > > I'm trying to minimise 600+ structure. They differ by an alanine
> > > > > substitution, which has been put in place using stateA/stateB
> > > topologies.
> > > > > The technique used to generate the initial structure was taken
> from:
> > > > >
> > > > http://pmx.mpibpc.mpg.de/output.pl?jobid=model_scanA_
> > > amber99sb-star-ildn-mut.ff_3329_20180703151957
> > > > > >
> > > > > >
> > > > > > This produces a topology of:
> > > > > >
> > > > > > stateA -> wildtype amino acid
> > > > > >
> > > > > > stateB -> alanine substitution
> > > > > >
> > > > > >
> > > > > > Given the number of structures, I am trying to automate
> everything.
> > > > > Centering, solvating, genion etc., all done. Now I come to an
> initial
> > > > > energy minimisation for each structure. Unfortunately, emtol is
> > aren't
> > > > > falling < 1000, which I find to be a value sufficient to move on
> from
> > > > > energy minimisation to more dynamical equilibrium methodologies.
> One
> > > > could
> > > > > argue that I should look at the trajectory, but I want the
> parameters
> > > > > correct first, especially given how I am automating this.
> > > > > >
> > > > > >
> > > > > > Since the alanine scan methodology generated stateA/stateB
> > topologies
> > > > > per structure, I figured that I need to use free energy parameters
> in
> > > my
> > > > > .mdp file to ensure that I am immediately only ever using the
> stateB
> > > > > (alanine) topology.
> > > > > >
> > > > > >
> > > > > > I basically need someone to sanity check the .mdp values to
> ensure
> > > that
> > > > > I only use stateB (the alanine topology) during the energy
> > > minimisation.
> > > > > The complete free energy .mdp values (from the mdout.mdp) file are:
> > > > > >
> > > > > >
> > > > > > ; Free energy variables
> > > > > > free-energy = yes
> > > > > > couple-moltype =
> > > > > > couple-lambda0 = vdw-q
> > > > > > couple-lambda1 = vdw-q
> > > > > > couple-intramol = no
> > > > > > init-lambda = -1
> > > > > > init-lambda-state = 0
> > > > > > delta-lambda = 0
> > > > > > nstdhdl = 10
> > > > > > fep-lambdas =
> > > > > > mass-lambdas =
> > > > > > coul-lambdas = 1.0
> > > > > > vdw-lambdas = 1.0
> > > > > > bonded-lambdas = 1.0
> > > > > > restraint-lambdas = 1.0
> > > > > > temperature-lambdas =
> > > > > > calc-lambda-neighbors = 1
> > > > > > init-lambda-weights =
> > > > > > dhdl-print-energy = no
> > > > > > sc-alpha = 0
> > > > > > sc-power = 1
> > > > > > sc-r-power = 6
> > > > > > sc-sigma = 0.3
> > > > > > sc-coul = no
> > > > > > separate-dhdl-file = yes
> > > > > > dhdl-derivatives = yes
> > > > > > dh_hist_size = 0
> > > > > > dh_hist_spacing = 0.1
> > > > > >
> > > > > > Please note, key-value pairs like coul-lambdas and vdw-lambdas
> are
> > > 1.0
> > > > > as I only want to model state B and I am not interested in slow
> > growth.
> > > > > >
> > > > > >
> > > > > > Are these parameters sufficient for modelling stateB upon
> immediate
> > > > > execution of an energy minimisation (and NPT/NVT dynamics)? I've
> had
> > > very
> > > > > little experience with the lambda implementation in gromacs and I
> > turn
> > > to
> > > > > more experience.
> > > > >
> > > > > They should, yes, but are you actually computing free energy
> changes?
> > > If
> > > > > this is just a hack to use a single starting structure and model
> Ala
> > in
> > > > > each position, that can certainly work, but the simulations will be
> > > > > slower (because there is overhead associated with the free energy
> > code)
> > > > > and you may face convergence issues like you're mentioning. If you
> > > don't
> > > > > need to compute DDG, then why not just mutate each residue and have
> > > > > normal PDB files to work with? Presumably the automation would be
> > just
> > > > > as easy, if not easier.
> > > > >
> > > > > -Justin
> > > > >
> > > > > --
> > > > > ==================================================
> > > > >
> > > > > Justin A. Lemkul, Ph.D.
> > > > > Assistant Professor
> > > > > Virginia Tech Department of Biochemistry
> > > > >
> > > > > 303 Engel Hall
> > > > > 340 West Campus Dr.
> > > > > Blacksburg, VA 24061
> > > > >
> > > > > jalemkul at vt.edu | (540) 231-3129
> > > > > http://www.thelemkullab.com
> > > > >
> > > > > ==================================================
> > > > >
> > > > > --
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