[gmx-users] PMF using umbrella sampling and Gromacs 5.0
Eudes Fileti
fileti at gmail.com
Tue Jul 28 13:59:20 CEST 2015
Dear Chris, thank you for help. I performed the test you suggested, with no
pressure coupling. Note that the behavior of the profile remained the same
even with no pressure coupling.
https://goo.gl/photos/2d8tsYFwp2eHCuCWA
The simulation parameters were exactly the same (except the sampling in the
test was 5 ns window and by coupling pressure, which was turned off).
Bests
eef
_______________________________________
Eudes Eterno Fileti
Instituto de Ciência e Tecnologia da UNIFESP
Rua Talim, 330, São José dos Campos - SP
Página: sites.google.com/site/fileti/
> ------------------------------
>
> Message: 2
> Date: Sun, 26 Jul 2015 02:45:50 +0000
> From: Christopher Neale <chris.neale at alum.utoronto.ca>
> To: "gmx-users at gromacs.org" <gmx-users at gromacs.org>
> Subject: Re: [gmx-users] PMF using umbrella sampling and Gromacs 5.0
> (Eudes Fileti)
> Message-ID:
> <
> BLUPR03MB184037E6EF2EC6D63BEBE21C58F0 at BLUPR03MB184.namprd03.prod.outlook.com
> >
>
> Content-Type: text/plain; charset="iso-8859-1"
>
> Dear Eudes:
>
> Glad that you solved one of the two issues. As for the bumps in the PMF, I
> have a new theory: the bumps come from pressure coupling. When the sampled
> distance, d, between the two molecules fluctuate a little closer than the
> center of restraint, d0, that adds a repulsive force that contributes to
> the virial and the box gets a little larger. Conversely, slight
> fluctuations of d that are larger than d0 will add a small bias to box
> contraction. This should be more noticeable when the restrained distance
> involves larger masses.
>
> It is at the moment unclear to me whether this might exert an effect
> indirectly due to overall system density or more directly as coordinate
> scaling impacts the instantaneous value of d. If it is the latter, then
> semi-isotropic pressure coupling, may also enhance the effect since the
> virial will be computed independently along the order parameter (I presume)
> and hence there is less noise from other dimensions.
>
> Can you please try again without pressure coupling (single precision
> should be fine for this test). Hopefully this is not the source of the
> bumps because, if it is affecting the PMF noticeably and the underlying
> free energy surface has a large gradient, then d will always be on one side
> of d0 and the effect will not be merely bumps but also some type of bias in
> the PMF. Whether this bias is accurate or artifactual falls outside of my
> mathematical abilities. The thing is, the force is a real force between
> real atoms so it seems like it really should be included in the virial (as
> it certainly is... I checked). I can tell you one thing for sure: the
> effect on box volume is real and noticeable. That is, if you look at the
> average system volume when d<<d0, it differs in a statistically significant
> manner from the average system volume when d>>d0 (something that I also
> checked).
>
> Thank you for looking into this further,
> Chris.
>
> ________________________________________
> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Eudes
> Fileti <fileti at gmail.com>
> Sent: 24 July 2015 16:47
> To: gromacs.org_gmx-users at maillist.sys.kth.se
> Subject: Re: [gmx-users] PMF using umbrella sampling and Gromacs 5.0
> (Eudes Fileti)
>
> Hello Chris, I write to report the results of the tests you suggested.
> To recap, I have two problems to solve. 1) The bad sampling around z = 0
> and 2) the bumps along to the profile.
>
> I solved the first discarding all the my initial configurations and
> performing a new pulling (SMD). Only this time I used a higher force
> constant (5000 kJ/mol nm2). Thus I got configurations close to z = 0, where
> they were not generated.
>
> For the second problem, you suggested recalculate the PMF using double
> precision. The results of this test showed that it does not solve the
> problem, on the contrary the bumps were even more pronounced, as indicated
> by the plot in this link. https://goo.gl/photos/wGNhdyNG9pdqGfcB6
>
> All tests were performed with prototypes simulations, with 40 windows of 2
> ns spaced by 0.1 nm. A larger sample is obviously necessary for reliable
> profiles, but this was enough to show the trend that I wanted to watch.
>
> As I have mentioned before, I've done several tests aiming to eliminate
> these bumps: use of higher sampling, up to 20ns per window; reducing the
> spacing between the windows (from 0.1 to 0.05 nm); changing the spring
> constant from 1000 up to 5000 kJ/mol nm2, use of two different versions of
> the Gromacs (4.6 e 5.0) and also I tested it with two different sets of
> initial settings.
>
> None of this attempts solved the bumps problem.
>
> If you (or someone else) have any other tips please let me know.
>
> Thank you
> eef
>
> _______________________________________
> Eudes Eterno Fileti
> Instituto de Ci?ncia e Tecnologia da UNIFESP
> Rua Talim, 330, S?o Jos? dos Campos - SP
> P?gina: sites.google.com/site/fileti/
>
> >
> > ------------------------------
> >
> > Message: 4
> > Date: Wed, 22 Jul 2015 14:56:50 +0000
> > From: Christopher Neale <chris.neale at alum.utoronto.ca>
> > To: "gmx-users at gromacs.org" <gmx-users at gromacs.org>
> > Subject: Re: [gmx-users] PMF using umbrella sampling and Gromacs 5.0
> > Message-ID:
> > <
> >
> BLUPR03MB18470A33A4E3FF149C95963C5830 at BLUPR03MB184.namprd03.prod.outlook.com
> > >
> >
> > Content-Type: text/plain; charset="iso-8859-1"
> >
> > Dear Eudes:
> >
> > There are two issues: The first issue is the fact that you've got a
> > sampling problem near the bilayer center. The second issue is the
> periodic
> > bumps that you see in your PMFs. I'll take the second part first.
> >
> > The source of the periodic bumps in PMFs from umbrella sampling is, to
> me,
> > a million dollar question. I've seen them in my own work. I've seen then
> in
> > the literature (as you noted for Fig. 4 in
> > http://www.mdpi.com/1422-0067/13/11/14451/htm ). I've seen them when
> > people use g_wham and Alan Grossfield's version of WHAM. What I don't yet
> > know is if people also see this when running US simulations with AMBER,
> > CHARMM, or NAMD. Frankly, either answer scares me a little. If you see
> wild
> > oscillations of the PMF, at large distances then one possible source is
> > that you are near a distance that is half your box length along the order
> > parameter. Note that with constant pressure simulations you will get
> > oscillations in the length of the box and also when your membrane changes
> > shape it could flip the vector of closest approach by 180 deg if you are
> > close to the half-box limit. However, that should not be relevant to the
> > bumps (out of interest, how large is your box along z?). Although I do
> > n't know what is going on with these PMF bumps, I also note that
> > membranes as a whole always tend to migrate toward positive z and lipids
> > tend to flow to positive x in gromacs simulations, so I wonder if it is a
> > rounding issue. Could you try again with double precision and see if you
> > get the bumps?
> >
> > As for the problem with sampling near the bilayer center... my first
> guess
> > is that you've got some of your replicas on the wrong side of the
> bilayer's
> > center. Did you intend to go across the center and sample also in the
> lower
> > leaflet? I've only ever used gromacs 3 and 4 to do pulling simulations,
> > never gmx 5. You can see my concerns about gmx5 for this type of issue
> near
> > the bilayer center here:
> >
> https://www.mail-archive.com/gromacs.org_gmx-users%40maillist.sys.kth.se/msg11324.html
> > One simply has to test it. However, if gmx5 does indeed work properly
> with
> > this new US philosophy, then I presume that you simply need to move your
> > starting coordinates such that your solute is in the positive leaflet for
> > all replicas. You can test this by visualization or g_dist, which reports
> > the sign of the displacement (look in the 5th column I think for the z
> > value). Note that you are using pull_start=yes, so which side of the
> > bilayer your solute is initially on should make a difference here.
> >
> > Chris.
> >
> > -- original message:
> >
> > Hi Chris, a few days ago I posted a question on GMX list but
> unfortunately
> > I not received an answer yet. So I write to you for help at your
> > convenience.
> > http://permalink.gmane.org/gmane.science.biology.gromacs.user/78439
> >
> > Besides the problem exposed the link above I'm trying to understand the
> > importance of the relative distance between the COM. Due to fluctuation
> in
> > the position of the center of mass position of the membrane, the minimum
> > distance is never zero, as shown in the graphs of my pulling below. What
> is
> > the effect of this difference in the calculation of the PMF? Could this
> be
> > the source of my problem?
> > https://goo.gl/photos/cwwLzog6wXAgVJG88
> >
> > Bests
> > eef
> >
> > PS. I found this paper below where authors have published this unusual
> > behavior (Figure 4). They did not explain the reason for the oscillations
> > at large distances and I also do not know why this occurs.
> > http://www.mdpi.com/1422-0067/13/11/14451/htm
> >
> >
> >
> > ________________________________________
> > From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> > gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Eudes
> > Fileti <fileti at gmail.com>
> > Sent: 18 July 2015 21:06
> > To: gmx-users at gromacs.org
> > Subject: [gmx-users] PMF using umbrella sampling and Gromacs 5.0
> >
> > Hello guys, I'm trying to calculate the PMF using umbrella sampling for a
> > small molecule to penetrate a lipid membrane. The 1D reaction coordinate
> is
> > along the z axis, which corresponds to the bilayer normal. The umbrella
> > potential acts on the center of mass of the molecule. The initial
> > configurations for each window, separated by a distance of 0.1nm, in a
> > range of 4 nm (distance between the centers of mass of the membrane and
> the
> > molecule), were obtained by a SMD.
> >
> > The umbrella potential was applied according to the parameters below (for
> > Gromacs version 5.0.3). Each window was sampled by 5 ns.
> >
> > ; COM PULLING
> > pull = umbrella
> > pull_geometry = direction
> > pull_dim = N N Y
> > pull_start = yes
> > pull-print-reference = no
> > pull_nstxout = 1000
> > pull_nstfout = 1000
> > pull_ngroups = 2
> > pull-ncoords = 1
> > ; Group name, weight (default all 1), vector, init, rate (nm/ps),
> > kJ/(mol*nm^2)
> > pull-group1-name = DPPC ; ref
> > pull-group2-name = LIG ; pulled
> > pull-coord1-groups = 1 2
> > pull-coord1-origin = 0 0 0
> > pull-coord1-vec = 0 0 1
> > pull-coord1-init = 0
> > pull-coord1-rate = 0.0
> > pull-coord1-k = 3000
> >
> > Histograms and the PMF obtained are shown in figure the link below.
> > https://goo.gl/photos/RkW9gbWrgeKEfV3R7
> >
> > I repeated the same test using other parameters (larger and small k
> values)
> > and options (cylinder and position, for this later I have used gmx 4.6)
> and
> > so far I could not get a satisfactory profile. In all tests, a problem
> that
> > I have observed is that the region near z = 0 is not sampled (there is a
> > gap between 0.0 and 0.5 nm). In addition the profile presents not smooth,
> > but somehow oscillating mainly for large z.
> >
> > As the gmx distance give a value different of zero for the smallest
> > distance of separation between the centers of mass (around 0.1-0.2 nm) I
> > believe that this weird behavior is related to the reference distance
> that
> > I have used.
> >
> > Could someone give me a light? Most of the tips I read in GMX list are
> > related to previous versions of the Gromacs and in a way the other tips
> > were already included in my tests.
> >
> > Thank you
> > eef
> >
> > _______________________________________
> > Eudes Eterno Fileti
> > Instituto de Ci?ncia e Tecnologia da UNIFESP
> > Rua Talim, 330, S?o Jos? dos Campos - SP
> > P?gina: sites.google.com/site/fileti/
> > --
> > Gromacs Users mailing list
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> >
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> ------------------------------
>
> Message: 3
> Date: Sun, 26 Jul 2015 10:15:51 +0100
> From: Dawid das <addiw7 at googlemail.com>
> To: gmx-users at gromacs.org
> Subject: Re: [gmx-users] Default cut-off scheme.
> Message-ID:
> <
> CAKSLqn60ybuXhuDjbgNDFDsm1caG4OqUFgeBcz4hg7xigJZijQ at mail.gmail.com>
> Content-Type: text/plain; charset=UTF-8
>
> Actually, I am working with Gromacs 4.6.7, but thank you for a tip ;).
> I forgot about the actual manual.
>
> All the best,
>
> Dawid Grabarek
>
> 2015-07-25 23:44 GMT+01:00 Mark Abraham <mark.j.abraham at gmail.com>:
>
> > On Sun, Jul 26, 2015 at 12:32 AM Tamisra Pal <tamisra1985 at gmail.com>
> > wrote:
> >
> > > Hi ,
> > >
> > > The cutoff-scheme by default is Verlet , unless you specify it as
> group.
> > > Yes , in this case , the ns_type is grid
> > >
> >
> > ... assuming this is version 5. But Dawid will get an accurate answer
> much
> > faster by consulting the manual for the version he is using ;-)
> >
> > Mark
> >
> >
> > > On Sun, Jul 26, 2015 at 1:33 AM, Dawid das <addiw7 at googlemail.com>
> > wrote:
> > >
> > > > Dear Gromacs Experts,
> > > >
> > > > I was issued with following minimize.mdp file:
> > > >
> > > > ; Minimization of bovine pancreatic trypsin inhibitor
> > > > title = minimization of BPTI
> > > > ; this is a comment
> > > > integrator = l-bfgs ; (other: cg, l-bfgs)
> > > > emtol = 500 ; convergence criterium- maximum value
> > of
> > > > force [kJ/(mol*nm)]
> > > > emstep = 0.01 ; initial step size [nm]
> > > > nsteps = 2000 ; number of steps
> > > > nstlist = 1 ; frequency update of neighbour list
> > > > ns_type = grid ; algorithm of updating neighbour
> list.
> > > It
> > > > seems to be cell list method.
> > > > nstenergy = 50 ;
> > > > rlist = 1.0
> > > > coulombtype = PME
> > > > rcoulomb = 1.0
> > > > rvdw = 1.0
> > > > pbc = xyz
> > > >
> > > > my question is what is the default cutoff-scheme here? group or
> > Verlet? I
> > > > assume there has to be default option because otherwhise nstlist and
> > > > ns_type will not make sense, won't they?
> > > > The other question is whether I understand ns_type=grid correctly. Is
> > it
> > > > cell list method as I commented?
> > > >
> > > > Best wishes,
> > > >
> > > > Dawid Grabarek
> > > > --
> > > > Gromacs Users mailing list
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> > > >
> > >
> > >
> > >
> > > --
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>
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