Hi Aravind,
Thanks for explaining some more details about the system.
I'm getting the impression that the helix unfolding is troubling you, but
maybe it's a reasonable transition between open and closed states?
What you describe above, with the energies increasing around the TS, while
the helix unfolds, seems pretty reasonable to me, but I don't know the
system's details.
What kind of path or results were you expecting that you are not getting?
Is there some indication (like from experiments) that there's a structure
at the transition state that you aren't seeing/sampling in the NEB?
After the high temperature sampling, when you are cooling down the
structures/beads near the transition state, does any secondary structure
reform (in the bead's trajectory, not over the course of the path)?
Feel free to send me images off-list if you'd like.
-Christina
On Wed, Oct 26, 2022 at 6:41 AM Aravind R via AMBER <amber.ambermd.org>
wrote:
> Hi Christina,
> Thanks for the detailed reply!
>
> > NEB is a path sampling method that's used to examine the transition
> > between two well-defined endpoints. It does not impose a barrier - the
> > system's transition over this barrier is the limiting factor in sampling
> > the open-to-close transition, and this is what/why you are trying to
> > calculate the path (and potential energy) independent of timescale.
> >
>
> I am trying to understand the interactions governing the open-to-close
> transition. Also, I have two test cases, where the Kon and Koff of these
> transitions are severely perturbed/changed. Once I understand one set of
> systems, I would like to compare it to the intermediate structure across
> the transition and transition energy. While I understand that Barrier
> height is not "imposed", I see the energy of the system increase while
> transitions and the corresponding structures from the trajectory show the
> complete unfolding of the helix (Structures attached). This "unfolding" is
> constant with the various number of images/ spring constant ranges
> attempted. This gave me the impression that Higher energy was forced.
>
> I do have a few additional suggestions, which may help:
> > -Try explicit solvent.
> >
>
> I was planning to do that once the protocol is standardised. But yes, I
> will continue with explicit solvent NEB.
>
> > -Extend the initial 1HEAT step to be more gradual (Try 1ns? 40ps is
> short,
> > and might be ok for alanine dipeptide but not for everything).
> >
> -Add an equilibration step after the first heating step (500 ps, 1 ns?)
> >
>
> I will try these. Also, the unfolding of the helix is mostly introduced
> while annealing (at 500K)
>
> > -Add images at the intermediate to try and avoid discontinuities in the
> > transition, this could help avoid those initial 'NaN' values.
> >
>
> I have tried this with various intermediates from TMD.
>
> Look at Test Case 3 in this paper and change up the original inputs to
> > match what they do (a similarly large system's protocol could be more
> > relevant to your own problem):
> > https://pubs.acs.org/doi/10.1021/acs.jctc.9b00329
> >
> Thanks for this suggestion. I will modify my protocol similar to that and
> try to get a good interpolating initial path.
>
> Regards,
> Aravind R
>
> >
> > On Fri, Oct 21, 2022 at 6:43 PM Christina Bergonzo <cbergonzo.gmail.com>
> > wrote:
> >
> >> Hi Aravind,
> >>
> >> NEB is a path sampling method that's used to examine the transition
> >> between two well-defined endpoints. It does not impose a barrier - the
> >> system's transition over this barrier is the limiting factor in sampling
> >> the open-to-close transition, and this is what/why you are trying to
> >> calculate the path (and potential energy) independent of timescale.
> >>
> >> It seems like you're doing some stuff to try and get this working for
> >> your system, like increasing/changing the number of starting images,
> >> generating intermediates using TMD, etc.
> >> There is no "standard" way to run these simulations, unfortunately. Each
> >> system is different, each underlying potential energy surface is
> different.
> >>
> >> I do have a few additional suggestions, which may help:
> >> -Try explicit solvent.
> >> -Extend the initial 1HEAT step to be more gradual (Try 1ns? 40ps is
> >> short, and might be ok for alanine dipeptide but not for everything).
> >> -Add an equilibration step after the first heating step (500 ps, 1 ns?)
> >> -Add images at the intermediate to try and avoid discontinuities in the
> >> transition, this could help avoid those initial 'NaN' values.
> >>
> >> Look at Test Case 3 in this paper and change up the original inputs to
> >> match what they do (a similarly large system's protocol could be more
> >> relevant to your own problem):
> >> https://pubs.acs.org/doi/10.1021/acs.jctc.9b00329
> >>
> >> The real struggle is getting a nice interpolating initial path. I'd
> >> recommend spending time on that first, then troubleshooting any other
> >> problems that arise.
> >>
> >> Good luck!
> >> -Christina
> >>
> >> On Fri, Oct 21, 2022 at 2:18 AM Aravind R via AMBER <amber.ambermd.org>
> >> wrote:
> >>
> >>> Hi Amber Developers/ Users,
> >>> I am performing NEB, moving the system from its "Open" structure to the
> >>> "Close" structure. This comprises of large conformational transition.
> >>> I had minimised the initial and final structures until convergence
> before
> >>> starting NEB.
> >>>
> >>> I have played around with spring constants ( skmin/skmax ranging from
> 0.5
> >>> to 50 at various stages), temperatures (slow to fast heating & slow
> >>> cooling) and the number of images to represent this transition (I
> >>> performed
> >>> TMD to sample images from open to close transition. Used conformations
> >>> from
> >>> TMD to represent the number of images I supply NEB to start with - I
> >>> used 8
> >>> - 64 images to represent transition with just 2 to 32 conformations
> from
> >>> TMD).
> >>>
> >>> I performed implicit solvent NEB in 6 stages:
> >>> 1HEAT - spring constant
> >>> ranging from 0.5 - 10 for 40ps of MD with a 0.5fs time step raising
> temp
> >>> from 0 to 300K
> >>> 2ANNEAL - spring constant
> >>> ranging from 1 - 50 for 1ns of MD with a 1fs time step raising temp
> from
> >>> 300 to 500K
> >>> 3EQUIL - spring constant
> >>> ranging from 1 - 50 for 2ns of MD with a 2fs time step equilibrating at
> >>> 500K
> >>> 4COOL - spring constant
> >>> ranging from 1 - 50 for 2ns of MD with a 2fs time step decreasing temp
> >>> from
> >>> 500 to 300K
> >>> 5EQUIL - spring constant
> >>> ranging from 1 - 50 for 2ns of MD with a 2fs time step equilibrating at
> >>> 300K
> >>> 6COOL - spring constant
> >>> ranging from 1 - 50 for 2ns of MD with a 2fs time step decreasing temp
> >>> from
> >>> 300 to 0K
> >>> 6EQUIL - spring constant
> >>> ranging from 1 - 50 for 2ns of MD with a 2fs time step equilibrating at
> >>> 0K
> >>> **spring constant ranging from x - y: is across different attempts not
> >>> in a
> >>> single simulation.
> >>> I am having the following issues:
> >>> 1) Irrespective of the values I play around with, NEB constantly
> >>> imposes a barrier height. This leads to the unfolding of the helix in
> the
> >>> region I try to perform the tgtrmsmask in.
> >>>
> >>> 2) At the images Where the conformational transition is sampled,
> the
> >>> energies go very high and the potential energy gets to NaN (This mostly
> >>> happens due to the helix unfolding raising dihedral and vdw energies to
> >>> shoot up).
> >>>
> >>> 3) Even though I used 32 evenly spaced conformers (sampling the
> >>> transition) from TMD to sample 64 images in NEB, the transition is not
> >>> smooth, with a sudden drop in energy for the last but one conformer.
> This
> >>> drop in energy moves towards the left as I decrease the number of
> >>> conformers I use to represent transition. For eg: If I just use open
> and
> >>> closed conformers (as in the tutorial), the dip in the energy is in the
> >>> centre image. As I increase the Conformers from TMD the dip move
> towards
> >>> the right from the centre. To negate this I tried an unequal number of
> >>> images used to represent transition: the first 4 images were sampled
> from
> >>> "Open" and the rest from "Close", and so on and so forth.
> >>>
> >>> Any help is appreciated !!!
> >>>
> >>> Regards,
> >>> Aravind R
> >>> _______________________________________________
> >>> AMBER mailing list
> >>> AMBER.ambermd.org
> >>> http://lists.ambermd.org/mailman/listinfo/amber
> >>>
> >>
> >>
> >> --
> >> -----------------------------------------------------------------
> >> Christina Bergonzo
> >> Research Chemist
> >> Biomolecular Measurement Division, MML, NIST
> >> -----------------------------------------------------------------
> >>
> >
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>
--
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Christina Bergonzo
Research Chemist
Biomolecular Measurement Division, MML, NIST
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Received on Wed Oct 26 2022 - 06:00:05 PDT
