[gmx-users] PMF using umbrella sampling and Gromacs 5.0
Christopher Neale
chris.neale at alum.utoronto.ca
Sun Aug 9 06:17:00 CEST 2015
http://membrane.urmc.rochester.edu/content/wham
________________________________________
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: 06 August 2015 07:09
To: gromacs.org_gmx-users at maillist.sys.kth.se
Subject: Re: [gmx-users] PMF using umbrella sampling and Gromacs 5.0
Dear Chris, thanks for the help.
Yes, I set the temperature properly.
Also I checked the line that you mentioned and it is exactly the same in my
version of gromacs (5.0.4).
I have not yet tried using another tool wham. I'll search the web and if I
find something, I report shortly.
eef
> Dear Eudes: then I return to being stumped. It sure looks like it might
be an issue with a constant
> somewhere. I'll note that v5.0.5 g_wham uses what I think is an incorrect
constant to convert to kcal
> (http://redmine.gromacs.org/issues/1787), but you're using kj so that
shouldn't be it. The gas constant
> defined by g_wham on line 1086 in v5.0.5 is also a little bit different
from the one used in core gromacs
> (for e.g. replica exchange to get the boltzmann constant), though again I
don't see how this could do
> anything but affect the overall scale by a tiny amount. However, I do
wonder about "8.314e-3" in lines like
> this where it possibly could affect
> the value: denom +=
invg*window[j].N[k]*exp(-U/(8.314e-3*opt->Temperature) + window[j].z[k]);
(line 966
> in calc_profile() in v5.0.5) Are you using g_wham? Can you try a
different wham software and see if you
> get the same thing? Also, are you setting -temp properly in g_wham ?
Beyond that, I've run out of ideas.
> If you do ever sort this out, I'd appreciate it if you could send me an
email off list to let me know (and post
> it here of course, I just don't always check the list).
> Thank you, Chris.
_______________________________________
Eudes Eterno Fileti
Instituto de Ciência e Tecnologia da UNIFESP
Rua Talim, 330, São José dos Campos - SP
Página: sites.google.com/site/fileti/
On 28 July 2015 at 08:59, Eudes Fileti <fileti at gmail.com> wrote:
> 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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>> > posting!
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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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>>
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