[gmx-users] restraints in PMF (Justin's tutorial)
chris.neale at utoronto.ca
chris.neale at utoronto.ca
Wed Jun 22 18:12:56 CEST 2011
Actually, this depends on what you are trying to achieve. If you
simply want to obtain the standard binding free energy, and somehow
you know that the bound state is represented by your umbrella at
dist=0 (via a crystal structure, for example), then using additional
restraints is common, acceptable, and in many cases desirable.
You can do this in analogy to, for example: D. L. Mobley, J. D.
Chodera, K. A. Dill. "On the use of orientational restraints and
symmetry number corrections in alchemical free energy calculations",
Journal of Chemical Physics 125:084902, 2006. Selected for the Virtual
Journal of Biological Physics Research 12(5), 2006.
Since the free energy is a state function, you are free to select any
pathway and it is useful to pick one that converges quickly... and
those involving rotation of large molecules are sure to converge very
slowly.
If you do this, then you'll need to account for the restraints in your
free energy term in a way similar to that outlined in the paper that I
referenced above.
The only reason that you would want to stick to the simple PMF is if
you are actually interested in the shape of the unrestrained PMF, in
which case you can't add additional restraints.
Chris.
-- original message --
Rebeca García Fandiño wrote:
> Thanks a lot for your quick answer!
> I think they are separated enough, however my monomers are cyclic
> (like discs); I start with a parallel conformation between then, but
> along the Umbrella simulation, both of them rotate and approach.
> If I do not use restraints, how could I avoid the rotation?
>
You don't. Why wouldn't two molecules rotate freely in solution when
binding or
unbinding? It seems like completely natural behavior. Even in simple systems
of protein-ligand association, part of the binding energy is the entropic
restriction of the ligand into a certain binding-competent pose. Why wouldn't
that happen here? Sounds like an artificial notion to me.
-Justin
> I am using the following md_umbrella.mdp:
>
> title = Umbrella pulling simulation
> define =
> define =
> ; Run parameters
> integrator = md
> dt = 0.002
> tinit = 0
> nsteps = 500000 ; 1 ns
> nstcomm = 10
> ; Output parameters
> nstxout = 5000 nstvout = 5000
> nstfout = 5000
> nstxtcout = 5000 nstenergy = 5000
> ; Bond parameters
> constraint_algorithm = lincs
> constraints = all-bonds
> continuation = yes
> ; Single-range cutoff scheme
> nstlist = 5
> ns_type = grid
> rlist = 1.4
> rcoulomb = 1.4
> rvdw = 1.4
> ; PME electrostatics parameters
> coulombtype = PME
> fourierspacing = 0.12
> fourier_nx = 0
> fourier_ny = 0
> fourier_nz = 0
> pme_order = 4
> ewald_rtol = 1e-5
> optimize_fft = yes
> ; Berendsen temperature coupling is on in two groups
> Tcoupl = Nose-Hoover
> tc_grps = r_1_r_2 CL3
> tau_t = 0.5 0.5
> ref_t = 300 300
> ; Pressure coupling is on
> Pcoupl = Parrinello-Rahman
> pcoupltype = isotropic
> tau_p = 1.0
> compressibility = 4.5e-5
> ref_p = 1.0
> ; Generate velocities is off
> gen_vel = no
> ; Periodic boundary conditions are on in all directions
> pbc = xyz
> ; Long-range dispersion correction
> DispCorr = EnerPres
> ; Pull code
> pull = umbrella
> pull_geometry = distance
> pull_dim = N N Y
> pull_start = yes
> pull_ngroups = 1
> pull_group0 = r_1
> pull_group1 = r_2
> pull_init1 = 0
> pull_rate1 = 0.0
> pull_k1 = 1000 ; kJ mol^-1 nm^-2
> pull_nstxout = 1000 ; every 2 ps
> pull_nstfout = 1000 ; every 2 ps
>
> Thanks a lot again for your help.
>
> Best wishes,
>
> Rebeca.
>
>
> > Date: Wed, 22 Jun 2011 10:53:16 -0400
> > From: jalemkul at vt.edu
> > To: gmx-users at gromacs.org
> > Subject: Re: [gmx-users] restraints in PMF (Justin's tutorial)
> >
> >
> >
> > Rebeca García Fandiño wrote:
> > > Hello,
> > > I am trying to obtain the PMF from Umbrella Sampling of the process of
> > > separating two monomers of a dimer, following Justin 's tutorial
> > >
> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html
> > >
> > > I have done the Umbrella Sampling simulations without using any
> > > restraints in any of the monomers, however, I can see that they move and
> > > gyrate so that although the c.o.m are separated from each other, there
> > > are parts of both interacting, in such way that they are not separated
> > > as they should be.
> > >
> > > Would it be correct if I apply restraints to both monomers in all the
> > > Umbrella Sampling simulations?. I have seen that in Justin's tutorial
> > > they applied restraints to one of the chains, but in my case I think I
> > > will need to restrain both of the units. Would that be correct for the
> > > PMF calculation?
> > >
> >
> > There are no position restraints applied during the umbrella sampling
> > simulations. They are unnecessary. The umbrella potential is itself a
> > restraint to maintain COM separation.
> >
> > If parts of your proteins are interacting, you simply haven't
> fully separated
> > your monomers and you need to create configurations with greater
> COM separation.
> > If you apply position restraints to fit some notion that your monomers
> > shouldn't interact at certain distances, then you're applying an
> unnatural (and
> > potentially incorrect) bias, causing the PMF to converge incorrectly.
> >
> > -Justin
> >
> > > Thanks a lot in advance.
> > >
> > > Rebeca.
> > >
> > > > Date: Mon, 20 Jun 2011 17:03:56 -0400
> > > > From: jalemkul at vt.edu
> > > > To: regafan at hotmail.com
> > > > CC: gmx-users at gromacs.org
> > > > Subject: Re: doubt about your Umbrella Sampling tutorial
> > > >
> > > >
> > > >
> > > > Rebeca García Fandiño wrote:
> > > > > Dear Justin,
> > > > > my name is Rebeca and I am a postdoctoral student in Santiago de
> > > > > Compostela University. Sorry for disturbing you to your personal
> > > mail, I
> > > > > have tried to post to the Gromacs-list first, but I did not get any
> > > answer.
> > > >
> > > > I was traveling and not paying much attention to messages across the
> > > list. I
> > > > will CC this reply to the list in the hopes that it is useful to
> > > others, as well.
> > > >
> > > > > I am trying to obtain the PMF from Umbrella Sampling of the
> process of
> > > > > separating two monomers of a dimer, following your tutorial, and I
> > > have
> > > > > a pair of doubts:
> > > > >
> > > > > 1)In this tutorial the generation of configurations is done using a
> > > .mdp
> > > > > file for pulling one chain from another, but is it possible to
> > > generate
> > > > > the configurations for Umbrella Sampling "by hand", I mean,
> > > changing the
> > > > > z coordinate of the monomer I want to move, then solvating and then
> > > > > minimizing these configurations? Is there any problem with this
> > > protocol
> > > > > for the obtaining of the configurations?
> > > > >
> > > >
> > > > No problem at all. The tutorial is but one possible method.
> > > >
> > > > > 2) I have noticed that you use restraints in the md_umbrella.mdp
> > > for the
> > > > > fixed chain. Is that correct? I can understand the restraints in the
> > > > > pulling simulations for generate starting configurations,
> but once you
> > > > > have the configurations, is is necessary to restrain one part of the
> > > > > system?
> > > > >
> > > >
> > > > Not usually. The tutorial presents a special case.
> > > >
> > > > > Thanks a lot in advance for your help with this topic, and thank you
> > > > > very much also for publishing this interesting tutorial. There was
> > > > > nothing useful until that for Umbrella Sampling with
> Gromacs 4.0, so I
> > > > > think it is more than wellcome for all Gromacs users!
> > > >
> > > > Glad they're useful :)
> > > >
> > > > -Justin
> > > >
> > > > > Best wishes,
> > > > > Rebeca.
> > > > >
> > > > > Dr. Rebeca García Fandiño
> > > > > Department of Organic Chemistry and Center for Research in
> Biological
> > > > > Chemistry
> > > > > and Molecular Materials
> > > > > Santiago de Compostela University
> > > > > E-15782 Santiago de Compostela (Spain)
> > > > > e-mail: rebeca.garcia.fandino at usc.es
> > > > > Phone: 34-981563100 ext 15760
> > > > >
> > > > >
> > > > >
> > > > >
> > > > >
> > > > >
> > > > >
> > > >
> > > > --
> > > > ========================================
> > > >
> > > > Justin A. Lemkul
> > > > Ph.D. Candidate
> > > > ICTAS Doctoral Scholar
> > > > MILES-IGERT Trainee
> > > > Department of Biochemistry
> > > > Virginia Tech
> > > > Blacksburg, VA
> > > > jalemkul[at]vt.edu | (540) 231-9080
> > > > http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin
> > > >
> > > > ========================================
> > >
> >
> > --
> > ========================================
> >
> > Justin A. Lemkul
> > Ph.D. Candidate
> > ICTAS Doctoral Scholar
> > MILES-IGERT Trainee
> > Department of Biochemistry
> > Virginia Tech
> > Blacksburg, VA
> > jalemkul[at]vt.edu | (540) 231-9080
> > http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin
> >
> > ========================================
> > --
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