[gmx-users] Performing energy minimisation for an alanine scan
Abhishek Acharya
abhi117acharya at gmail.com
Mon Jul 9 14:19:11 CEST 2018
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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