Are you using the Monte Carlo barostat? We regularly use this with both
relative and (restrained) absolute transformations. It's possible that the
virials need for Berendsen calculations are not quite right.
Brian
On Sat, Apr 11, 2020, 5:23 AM Juraj Dobias <juraj.dobias.uochb.cas.cz>
wrote:
> Hi all,
>
> Thank you all for your suggestions. My protocol is finally working well.
> I don't need any restraints. The key was to use NPT ensemble in case of
> unrestrainted simulation. It is pretty obvious that GPU code does not
> work properly with NPT ensemble. I don't think this limitation is widely
> known within Amber comunity, because It took me 5 days of reading
> articles and googling to figure it out. But in the end, its not a
> disaster, because NVT ensemble has better performance. For my system 75
> ns/day instead of 50 ns/day.
>
> In order to use NVT, density needs to be equilibriated before. For that,
> you can use NPT with restrained ligands with GPU code or CPU code
> without restraints. 100 ps is usually enough, so CPU code is not a problem.
>
> All the best,
>
> Juraj
>
> On 10. 04. 20 17:46, Debarati DasGupta wrote:
> > Hello Qinghua,
> >
> > I do have restraints applied on all steps of the protocol so that ligand
> is tethered to the spot of interest.
> > Thanks!
> >
> > Sent from Mail<https://go.microsoft.com/fwlink/?LinkId=550986> for
> Windows 10
> >
> > From: Qinghua Liao<mailto:scorpio.liao.gmail.com>
> > Sent: 10 April 2020 18:14
> > To: amber.ambermd.org<mailto:amber.ambermd.org>
> > Subject: Re: [AMBER] Ligand leaving binding site at high lambdas using
> TI softcore
> >
> > Hello,
> >
> > For absolute binding free energy calculation, some restraints might be
> > necessary,
> > related discussion is available in this chapter:
> > https://link.springer.com/protocol/10.1007%2F978-1-4939-7756-7_11
> >
> >
> > All the best,
> > Qinghua
> >
> > On 4/10/20 2:13 PM, Debarati DasGupta wrote:
> >> Hi Juraj,
> >>
> >> I have been trying to calculate the absolute binding free energies of a
> small molecule to my kinase protein and I have faced issues too with the
> NPT equilibration steps on GPUs. The cpu version runs stable. Does that
> indicate there may be a bug in the GPU code using NPT ensemble?
> >> Well since I could not equilibrate my complex at higher lambdas, I am
> stuck at the phase and I m trying to make things work.
> >> I have a paper which does TI on gPUs and succeeds; thought it might
> help you in setting up the protocol better.
> >> This is the link https://doi.org/10.1021/acs.jcim.9b00105
> >>
> >> Thanks,
> >> Debarati
> >>
> >>
> >>
> >> From: Juraj Dobias<mailto:juraj.dobias.uochb.cas.cz>
> >> Sent: 10 April 2020 02:04
> >> To: amber.ambermd.org<mailto:amber.ambermd.org>
> >> Subject: Re: [AMBER] Ligand leaving binding site at high lambdas using
> TI softcore
> >>
> >> Hi Callum,
> >>
> >> Thanks for your response.
> >>
> >> I can confirm, that when ligand change is smaller system is more stable.
> >> For example changing Cl on benzene to H was stable until lambda 0.7.
> >>
> >> I am also using Amber18 GPU. I use CPU code for NVT heating and first
> >> NPT equilibration, as GPU code had problems with large cell volume
> changes.
> >>
> >> Sometimes ligands became entangled inside protein and then rip it apart.
> >> I think decoupled ligand goes deeper to the protein which would be
> >> normal, but then coupled ligand coordinates are resynchronized with
> >> decoupled one, protein is deformed, allowing decoupled ligand to go even
> >> deeper and process repeats. At low lambdas this is not happening because
> >> coordinates are synchronized always to first ligand which is in case of
> >> low lambda more coupled one.
> >>
> >> After your suggestion, I tried 100 ns NVT production run and ligand was
> >> stable at lambda 0.9 which is great. Then I also tried same NPT
> >> production run as before but using CPU pmemd.MPI instead of pmemd.cuda
> >> and again ligand was stable. This might suggest a bug in GPU code using
> >> NPT ensemble and TI.
> >>
> >> Juraj
> >>
> >> On 09. 04. 20 21:00, Dickson, Callum wrote:
> >>> Hi Juraj,
> >>>
> >>> I have recently been trying out TI simulations and have observed the
> same behaviour. I am by no means an expert at free energy runs so I'd be
> interested to hear advice from others.
> >>>
> >>> This was occurring for me when the TI regions were large (different
> transformations with smaller TI regions did not result in ligands flying
> away). In NPT ensemble, certain ligands would immediately leave the pocket.
> The same system in NVT ensemble was more stable, without the ligand
> drifting away. I am using the Amber18 GPU code, fully patched.
> >>>
> >>> Do you see this behaviour also with NVT production run?
> >>>
> >>> Best,
> >>> Callum
> >>>
> >>>
> >>> -----Original Message-----
> >>> From: Juraj Dobias <juraj.dobias.uochb.cas.cz>
> >>> Sent: Thursday, April 9, 2020 1:30 PM
> >>> To: amber.ambermd.org
> >>> Subject: Re: [AMBER] Ligand leaving binding site at high lambdas using
> TI softcore
> >>>
> >>> To make it clearer. As I understand TI, simulation at 0.1 lambda
> should be in principle equivalent to simulation at 0.9 lambda with switched
> endstates, is it correct?
> >>>
> >>> I think problem is that coordinates of common atoms in each TI regions
> are changed independently during simulation (I thought it is not
> >>> possible) and then resynchronized, so that coordinates from T1 are
> copied to T2.
> >>>
> >>> Coordinates for common atoms in starting pdb are exactly equal, but I
> observe these warnings starting in equil3 (restraining for is smaller than
> before)
> >>>
> >>> WARNING: Local coordinate 6005 differs from partner coordinate
> 6035 !
> >>> Deviation is small, changing partner coordinate.
> >>>
> >>> If I define whole ligands as softcore, simulation works as expected.
> But it is not ideal, because low coupled ligand becomes unstable.
> >>>
> >>>
> >>> On 08. 04. 20 22:39, Juraj Dobias wrote:
> >>>> Dear all,
> >>>>
> >>>> I am trying to utilize TI in amber in our medicinal chemistry project.
> >>>> I successfully did tutorial of transforming benzene to phenol, but I
> >>>> am struggling for a week with my system.
> >>>>
> >>>> Problem is that ligands have higher tendency to immediately leave
> >>>> binding site after releasing restraints at higher lambda values.
> >>>>
> >>>> My workflow is:
> >>>>
> >>>> 10000 steps of minimization (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__min.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=e0q7Xe4kHAxgfod1sPVqnh1HKrl2UP7fk2UxfyKkVCE&e=
> )
> >>>>
> >>>> 50 ps heating with restrained solute heavy atoms with force constant
> >>>> 100 (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__heat.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=NLeEZSyD66QJIdPVE5AbQelZVRFwVKDwhLHer2UntN0&e=
> )
> >>>>
> >>>> 50 ps npt with restrained solute heavy atoms with force constant 100
> >>>> (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__equil1.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=hPB98VnDPjWWhLtRU6TZvLwlkRt0tuHJPlLztaiC5yM&e=
> )
> >>>>
> >>>> 100 ps npt with restrained solute heavy atoms with force constant 10
> >>>> (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__equil2.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=xGceI4OdNjaGchBjvtNilphqBEDaMp3B2HpDUHg6IhM&e=
> )
> >>>>
> >>>> 100 ps npt with restrained protein backbone and core TI region with
> >>>> force constant 10 (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__equil3.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=BFfEgRfukbu-Hu1ZkCjo5KJi4OvfqxT9eiXg0ZcchWI&e=
> )
> >>>>
> >>>> 100 ps npt with restrained protein backbone and core TI region with
> >>>> force constant 1 (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__equil4.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=3KwNrn-fMGnA_Fj1GdlUYqjNEzAo4ytUDD_cdecr6GM&e=
> )
> >>>>
> >>>> 100 ps npt without restraints (
> https://urldefense.proofpoint.com/v2/url?u=http-3A__prod.in&d=DwIGaQ&c=ZbgFmJjg4pdtrnL2HUJUDw&r=HwsFjSfOtLupDR-NuCP430rdz1DD2LkJxNM3BsKSjrw&m=ENVyFj6_oD0p_qmj-WymfucA1YgEb6nnnRKPbWF9MfA&s=7XD5Q06IvkvqIxudn9B0QZ1dIyUXTrF-R0uCizZR9bI&e=
> )
> >>>>
> >>>> See attached files.
> >>>>
> >>>> My plan was to use this small production run with 0.5 lambda to
> >>>> generate starting structures for other runs and windows, but for most
> >>>> of tried ligands, I am getting them out of pocket in first few
> >>>> picoseconds even at lambda 0.5.
> >>>>
> >>>> I know that both endstates are stable under normal MD for 100 ns
> >>>> without problem. If I perform whole workflow for lambda 0.1 and 0.9 -
> >>>> the production with 0.1 is stable. If I switch ligands and repeat
> >>>> procedure again production with lambda 0.1 is stable, but of course
> >>>> with different ligand as more dominant. I tried to play with number of
> >>>> steps during preparation, different SHAKE settings, using CPU or GPU
> >>>> code and more with no luck.
> >>>>
> >>>> I think I am missing something important :) Any help would be
> >>>> appreciated.
> >>>>
> >>>> Juraj Dobias
> >>>>
> >>>>
> >>>>
> >>>>
> >>>> _______________________________________________
> >>>> AMBER mailing list
> >>>> AMBER.ambermd.org
> >>>>
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Received on Sat Apr 11 2020 - 08:30:03 PDT
