Dear Thomas and all,
In my case, between the two redox-states, there is a charge difference in
the cofactor-covalently attached to the protein.
And because I'm neutralizing the system, tleap adds one Cl- anion extra
when the co-factor is more positive compared to the other redox-state.
So my question is, is it meaningful to simulate a system with non-zero
net-charge (+1 in this case) and compare the energies with a neutral system
(which has an equal number of protein, water, ion and co-factor atoms)? If
yes, I'm thinking of generating a matrix of potential energy differences
(printed in mdout files) between all the snapshots. Will the generation of
multiple trajectories for both systems and then re-estimating this E-matrix
be able to deal with the noise?
I'm reading your papers carefully with the hope that the answers might be
already there.
Nevertheless, I rephrased my question(s) here with the hope that other
experts on the list might also give valuable suggestions.
Thanks a lot for valuable comments/suggestions.
Best regards.
On Thu, Oct 8, 2020 at 8:17 AM Thomas Cheatham <tec3.utah.edu> wrote:
> As Carlos mentioned, you cannot compare energies of different molecular
> systems that are not directly the same composition. But, if you built a
> system with the ion-protein bound vs. ion-free with exactly the same number
> of waters you could compare energies, but this requires a large number of
> frames and is very noisy. We did this in this work with explicit water
> included: http://pubs.acs.org/doi/abs/10.1021/ci500132c and also this
> work in an MM-PBSA context:
> https://www.cell.com/biophysj/fulltext/S0006-3495(03)74608-6
>
> -tec3
>
> > I think I understand the point Carlos mentioned.
> > I'm getting meaningful continuum solvation energy differences after
> > stripping the water and ions.
> > But I'm still trying to understand if there's some way to estimate the
> > differences in solvent and protein reorganization energies between two
> > states with just one charge difference using the explicit solvent MD
> > trajectories.
> >
> > Looking forward to receiving valuable suggestions and advice from the
> list.
> > Thanks for the valuable suggestions and comments.
> > Best regards.
> >
> > On Sat, Oct 3, 2020, 18:46 Carlos Simmerling <
> carlos.simmerling.gmail.com>
> > wrote:
> >
> >> In general, molecular mechanics absolute energies cannot be compared for
> >> different molecules or systems. The zero is arbitrary and only relative
> >> energies of a given system are meaningful. The conformations sampling
> can
> >> be compared, using the methods discussed earlier in this thread.
> >>
> >> On Fri, Oct 2, 2020, 5:12 PM Vaibhav Dixit <vaibhavadixit.gmail.com>
> >> wrote:
> >>
> >>> Dear all,
> >>> This is troubling since it seems to kill the very purpose for which I
> >>> started to build the two states for the system.
> >>> Moreover the assumption that they have equal number of water molecules
> >> also
> >>> seems incorrect because while adding the extra ion to neutralize the
> >> system
> >>> tleap must have removed some water molecules that are present in the
> >>> trajectory.
> >>>
> >>> I think it is possible to add equal number of ions in both the systems.
> >>> That will keep the number of water molecules also same and make the
> >> energy
> >>> comparable. But I'm not sure if I it is meaningful to simulate a system
> >>> with net 1 negative charge. Will it create instabilities during the MD
> >>> simulations? Are sander and pmemd and other tools expected to handle
> this
> >>> correctly? I think so but can someone please confirm.
> >>>
> >>> Please suggest and help me decide the best possible way to simulate the
> >>> charge difference and the estimate difference in other measurable
> >>> properties.
> >>>
> >>> Thank you and best regards.
> >>> Vaibhav
> >>>
> >>> On Fri, Oct 2, 2020, 22:01 Carlos Simmerling <
> >> carlos.simmerling.gmail.com>
> >>> wrote:
> >>>
> >>>> I'm not sure I see a way to compare energies, the extra ion will
> >> interact
> >>>> with everything else due to PME, and if you delete it you'll have a
> >> hole
> >>>> that the other system won't have that likely will shift the energies
> >> for
> >>>> the water. You could strip all water and ions and compare energies in
> a
> >>>> continuum model, but you'd need to decide if that approximation is ok
> >> or
> >>>> not.
> >>>> maybe others have better ideas here...
> >>>> carlos
> >>>>
> >>>> On Fri, Oct 2, 2020 at 11:42 AM Vaibhav Dixit <
> vaibhavadixit.gmail.com
> >>>
> >>>> wrote:
> >>>>
> >>>>> Dear All,
> >>>>> these are helpful suggestions, thanks Carlos,
> >>>>> After these commands, I assume that, if I load the trajectory for
> >> the
> >>>> 2nd
> >>>>> structure and give similar rmsd commands, I should be able to see how
> >>> it
> >>>>> evolves during MD simulation, right? Then I hope I can see/compare
> >> them
> >>>> in
> >>>>> one plot may be using gnuplot (xmgrace is not working on my Centos
> >> 7).
> >>>>>
> >>>>> How can I handle this incompatibility between prmtops while
> >> estimating
> >>>> the
> >>>>> Es with imin=5 of one structure with parameters for the other
> >>> (parameters
> >>>>> are different only for the co-factor and residues coordinating with
> >> it
> >>> in
> >>>>> addition to the difference of the extra ion)?
> >>>>>
> >>>>> I hope that these questions are meaningful and I'll get valuable
> >>>>> suggestions to tackle the same.
> >>>>>
> >>>>> Thank you and best regards :)
> >>>>> Vaibhav
> >>>>>
> >>>>> On Fri, Oct 2, 2020 at 8:37 PM Carlos Simmerling <
> >>>>> carlos.simmerling.gmail.com> wrote:
> >>>>>
> >>>>>> cpptraj will allow you to specify a different prmtop and
> >>>>>> reference coordinate set when doing RMSD calculations... it can get
> >>>>>> complicated if atoms don't match up, but your case sounds like a
> >>> single
> >>>>>> atom mask will give the same selection for both systems so it
> >> should
> >>>> work
> >>>>>> smoothly. Dan Roe or others might have more detailed advice, but
> >> this
> >>>>> works
> >>>>>> for me.
> >>>>>>
> >>>>>> I use something like this in my cpptraj script.
> >>>>>> load both prmtops, with a label for the alternate one
> >>>>>>
> >>>>>> parm ./prmtop
> >>>>>> parm ../build_40/prmtop [refparm]
> >>>>>>
> >>>>>> define reference structures, indicating the alternate prmtop for
> >> the
> >>>>> other
> >>>>>> system, and label each reference structure for use later:
> >>>>>>
> >>>>>> reference ./1min.rst7 [refinit]
> >>>>>> reference ../build_40/struct40.rst7 parm [refparm] ref [ref40]
> >>>>>>
> >>>>>> trajin ./md.x
> >>>>>>
> >>>>>> calculate rmsd to the SAME system:
> >>>>>>
> >>>>>> rmsd rms1 :10-70.CA,N,C,O out rmsd.10-70.dat ref [refinit]
> >>>>>>
> >>>>>> and then when doing the rmsd to the alternate system:
> >>>>>>
> >>>>>> rmsd rms2 :10-70.CA,N,C,O out rmsd.10-70.ref40.dat ref [ref40]
> >>>>>>
> >>>>>> On Fri, Oct 2, 2020 at 10:56 AM Vaibhav Dixit <
> >>> vaibhavadixit.gmail.com
> >>>>>
> >>>>>> wrote:
> >>>>>>
> >>>>>>> Dear Amber developers and users,
> >>>>>>> I have two structures identical except for a difference in
> >>> co-factor
> >>>>>>> charge.
> >>>>>>> Thus one has a Cl- ion extra added by tleap, but the number of
> >>>>>>> protein, non-standard residue and water atoms are identical.
> >>>>>>> Now, how do I compare the rmsd of the two trajectories snapshot
> >> by
> >>>>>>> snapshot?
> >>>>>>> Both trajectories start from the same PDB, thus I want to check
> >> if
> >>>> (how
> >>>>>>> much) there is a divergence in the coordinate-space that they
> >>> sample
> >>>> as
> >>>>>>> they move along the MD trajectories.
> >>>>>>> Is it possible/meaningful to compare reorganization of waters and
> >>> AA
> >>>>>>> between the two trajectories w.r.t. to coordinates and energies?
> >>> As
> >>>>>>> suggested earlier I will try to use imin=5 for this, but first I
> >>>> think
> >>>>> I
> >>>>>>> need to resolve incompatibility due to the extra Cl- ion. Both
> >> Cl-s
> >>>>> are >
> >>>>>>> 10 A from cofactor, so is it safe to simply ignore them and
> >> delete
> >>>> from
> >>>>>>> both prmtop before rmds or other analysis?
> >>>>>>>
> >>>>>>> I tried to use cpptraj to estimate rmsd for one trajectory using
> >>>> prmtop
> >>>>>> of
> >>>>>>> another which failed (then realized the small but important
> >>>> difference
> >>>>>>> between the two).
> >>>>>>> Is it possible to simply delete the extra/both Cl- from prmtop
> >> with
> >>>>>> parmed
> >>>>>>> and will it then work with cpptraj for all kinds of analysis.
> >>>>>>> Please suggest.
> >>>>>>> Looking forward to valuable suggestions from the list on this.
> >>>>>>> thank you and best regards.
> >>>>>>>
> >>>>>>>
> >>>>>>> --
> >>>>>>>
> >>>>>>> Regards,
> >>>>>>>
> >>>>>>> Dr. Vaibhav A. Dixit,
> >>>>>>>
> >>>>>>> Visiting Scientist at the Manchester Institute of Biotechnology
> >>>> (MIB),
> >>>>>> The
> >>>>>>> University of Manchester, 131 Princess Street, Manchester M1 7DN,
> >>> UK.
> >>>>>>> AND
> >>>>>>> Assistant Professor,
> >>>>>>> Department of Pharmacy,
> >>>>>>> ▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄
> >>>>>>> Birla Institute of Technology and Sciences Pilani (BITS-Pilani),
> >>>>>>> VidyaVihar Campus, street number 41, Pilani, Rajasthan 333031.
> >>>>>>> India.
> >>>>>>> Phone No. +91 1596 255652, Mob. No. +91-7709129400,
> >>>>>>> Email: vaibhav.dixit.pilani.bits-pilani.ac.in,
> >>>> vaibhavadixit.gmail.com
> >>>>>>> http://www.bits-pilani.ac.in/pilani/vaibhavdixit/profile
> >>>>>>> https://www.linkedin.com/in/vaibhav-dixit-b1a07a39/
> >>>>>>>
> >>>>>>> ORCID ID: https://orcid.org/0000-0003-4015-2941
> >>>>>>>
> >>>>>>>
> >>> http://scholar.google.co.in/citations?user=X876BKcAAAAJ&hl=en&oi=sra
> >>>>>>>
> >>>>>>> P Please consider the environment before printing this e-mail
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> >>>>>
> >>>>>
> >>>>> --
> >>>>>
> >>>>> Regards,
> >>>>>
> >>>>> Dr. Vaibhav A. Dixit,
> >>>>>
> >>>>> Visiting Scientist at the Manchester Institute of Biotechnology
> >> (MIB),
> >>>> The
> >>>>> University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
> >>>>> AND
> >>>>> Assistant Professor,
> >>>>> Department of Pharmacy,
> >>>>> ▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄
> >>>>> Birla Institute of Technology and Sciences Pilani (BITS-Pilani),
> >>>>> VidyaVihar Campus, street number 41, Pilani, Rajasthan 333031.
> >>>>> India.
> >>>>> Phone No. +91 1596 255652, Mob. No. +91-7709129400,
> >>>>> Email: vaibhav.dixit.pilani.bits-pilani.ac.in,
> >> vaibhavadixit.gmail.com
> >>>>> http://www.bits-pilani.ac.in/pilani/vaibhavdixit/profile
> >>>>> https://www.linkedin.com/in/vaibhav-dixit-b1a07a39/
> >>>>>
> >>>>> ORCID ID: https://orcid.org/0000-0003-4015-2941
> >>>>>
> >>>>> http://scholar.google.co.in/citations?user=X876BKcAAAAJ&hl=en&oi=sra
> >>>>>
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--
Regards,
Dr. Vaibhav A. Dixit,
Visiting Scientist at the Manchester Institute of Biotechnology (MIB), The
University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
AND
Assistant Professor,
Department of Pharmacy,
▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄▄
Birla Institute of Technology and Sciences Pilani (BITS-Pilani),
VidyaVihar Campus, street number 41, Pilani, Rajasthan 333031.
India.
Phone No. +91 1596 255652, Mob. No. +91-7709129400,
Email: vaibhav.dixit.pilani.bits-pilani.ac.in, vaibhavadixit.gmail.com
http://www.bits-pilani.ac.in/pilani/vaibhavdixit/profile
https://www.linkedin.com/in/vaibhav-dixit-b1a07a39/
ORCID ID: https://orcid.org/0000-0003-4015-2941
http://scholar.google.co.in/citations?user=X876BKcAAAAJ&hl=en&oi=sra
P Please consider the environment before printing this e-mail
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Received on Wed Oct 07 2020 - 21:00:03 PDT
