VMD-L Mailing List

From: francesco quilli (quilli.1855253_at_studenti.uniroma1.it)
Date: Thu Mar 21 2024 - 08:27:40 CDT

 Thank you all for the prompt responses and the various approaches to the
problem.

As advised by you, I have researched the dihedrals related to the one to be
optimized.I used the Torsion Explorer tool, which allows for trajectory
analysis. From there, I selected several dihedrals associated with the
first minimum of the PES that I am unable to fit. I performed the
calculations and conducted several optimization attempts, but they didn't
lead to significant improvements. Overall, the RMSE is slightly lower, but
none of the MM profiles reach that minimum. I really appreciate your help
and attention to my issue.

Best regards,

Francesco Quilli

Il giorno ven 15 mar 2024 alle ore 00:23 Klimkowski, V <vklimkow_at_butler.edu>
ha scritto:

> It might be worth 1st getting it out of the spiro compound, refining
> the dihedrals & then using these refined parameters as the starting point
> to rerefine the spiro compound. Specifically breaking the CH2-CH2 bond in
> the dioxolane, & refining the CH2-C-O-CH3 dihedral.
>
> Additionally, look at this article for some ideas:
> https://urldefense.com/v3/__https://doi.org/10.1007/s10822-022-00464-3__;!!DZ3fjg!59h26ewiQozi1-_5R1s5wDhX3BS3UmdXQJ7JlP5vEqJCp4ICCmo80wn6EkkPjxjWnbU2RgczJQQUcnR0kVguUJ0rcQMWtNpfFBAf-A$
> See what special considerations they used to refine these fused ring
> compounds.
>
> Interesting Problem. Best,
> V Joe Klimkowski, PhD
> Chemistry Research Affiliate
> Butler University
> Indianapolis, IN
> <https://urldefense.com/v3/__https://doi.org/10.1007/s10822-022-00464-3__;!!DZ3fjg!59h26ewiQozi1-_5R1s5wDhX3BS3UmdXQJ7JlP5vEqJCp4ICCmo80wn6EkkPjxjWnbU2RgczJQQUcnR0kVguUJ0rcQMWtNpfFBAf-A$ >
> On the force field optimisation of $$\\beta$$ β -lactam cores using the
> force field Toolkit - Journal of Computer-Aided Molecular Design
> <https://urldefense.com/v3/__https://doi.org/10.1007/s10822-022-00464-3__;!!DZ3fjg!59h26ewiQozi1-_5R1s5wDhX3BS3UmdXQJ7JlP5vEqJCp4ICCmo80wn6EkkPjxjWnbU2RgczJQQUcnR0kVguUJ0rcQMWtNpfFBAf-A$ >
> When employing molecular dynamics (MD) simulations for computer-aided drug
> design, the quality of the used force fields is highly important. Here we
> present reparametrisations of the force fields for the core molecules from
> 9 different $$\\beta$$ β -lactam classes, for which we utilized the force
> field Toolkit and Gaussian calculations. We focus on the parametrisation of
> the dihedral angles, with the goal of reproducing the optimised quantum
> geometry in MD simulations. Parameters taken from CGenFF turn out to be a
> good initial guess for the multiplicity of each dihedral angle, but the key
> to a successful parametrisation is found to lie in the phase shifts. Based
> on the optimised quantum geometry, we come up with a strategy for
> predicting the phase shifts prior to the dihedral potential fitting. This
> allows us to successfully parameterise 8 out of the 11 molecules studied
> here, while the remaining 3 molecules can also be parameterised with small
> adjustments. Our work highlights the importance of predicting th
> doi.org
>
> ------------------------------
> *From:* owner-vmd-l_at_ks.uiuc.edu <owner-vmd-l_at_ks.uiuc.edu> on behalf of
> Gumbart, JC <gumbart_at_physics.gatech.edu>
> *Sent:* Thursday, March 14, 2024 8:18 AM
> *To:* Daniel Fellner <dfel694_at_aucklanduni.ac.nz>
> *Cc:* francesco quilli <quilli.1855253_at_studenti.uniroma1.it>; Ernesto
> Aleksei Delgado Hurtado <ERDELGADO_at_udec.cl>; VMD Mailing List <
> vmd-l_at_ks.uiuc.edu>
> *Subject:* Re: vmd-l: FFTK - Dihedral doesn't fit the QM target data
>
> Agreed, there may be be a missing parameter or two that’s leaving it
> unable to fit that first minimum.
>
> Best,
> JC
>
> On Mar 14, 2024, at 4:51 AM, Daniel Fellner <dfel694_at_aucklanduni.ac.nz>
> wrote:
>
> There may be other correlated dihedrals which also require simultaneous
> fitting, even if they have low penalty scores, this usually fixes the
> problem for me.
>
> *Daniel Fellner BSc(Hons)*
> PhD Candidate | Research Assistant
> School of Chemical Sciences
> University of Auckland
> Ph +64211605326
>
>
> On Thu, 14 Mar 2024 at 21:06, francesco quilli <
> quilli.1855253_at_studenti.uniroma1.it> wrote:
>
> Thanks for the prompt responses,
>
> The dioxa azaspiro group is already a fragment of a larger molecule; the
> dihedral of interest is located at the center of this group, and it is
> impossible to fragment it further.
>
> I analyzed the rotation using the Torsion Explorer tool, and the generated
> conformations do not seem to present steric clashes.
>
>
> As recommended, I conducted tests with a smaller step size: Scan +-90°
> Step size 5° and Scan +-90° Step size 3°. As can be observed from the PES
> scans (PES profiles are shown in CG321_CG321_CG3C50_OG3C51.pdf), not much
> has changed since the previous tests (Scan +-90° Step size 15° and Scan
> +-90° Step size 10°), and the problem persists. I would appreciate your
> advice on what I could try to improve these PES profiles.
>
>
> Best regards,
> Francesco
>
>
> Il giorno mar 12 mar 2024 alle ore 03:43 Gumbart, JC <
> gumbart_at_physics.gatech.edu> ha scritto:
>
> Indeed, it’s possible that steric clashes are interfering with the
> rotation, which creates those somewhat unusual PMFs. But at the very
> least, decreasing the step size is a good idea. The PMFs look rough.
>
> Best,
> JC
>
> On Mar 11, 2024, at 6:21 PM, Ernesto Aleksei Delgado Hurtado <
> ERDELGADO_at_UDEC.CL> wrote:
>
> Hi francesco
> I can tell by the shape of your PES scans that you are trying to fit your
> parameters using the whole molecule.
> The recommended approach is by dividing your molecules into smaller pieces
> that contain your functional groups of interest, fitting your parameters on
> those molecules and then copying the parameters to use on your whole
> molecule.
> Regards,
> Ernesto Delgado
> El 11/3/24 a las 12:12, francesco quilli escribió:
>
> Hi all,
>
> I am currently working on resolving a dihedral belonging to a dioxa
> azaspiro group. I have generated the QM target data, but I am encountering
> difficulties in fitting the dihedral to the target.
> I utilized the CGenFF program to identify entities with high penalties that
> require further validation/optimization. Based on the output of CGenFF:
>
>
> dihedral {CG321 CG321 CG3C50 OG3C51} K=3.4000 Periodicity 1 Phase shift=
> 180° Penalty=53;
>
>
> I initiated a ±90° scan with a 15° step size. I attempted various
> combinations (i.e., periodicities, phase shift angles, and optimization
> algorithms as you can see in CG321_CG321_CG3C50_OG3C51.pdf), but I am
> unable to reduce the RMSE beyond 1.769. Additionally, in the target data, I
> observe a first minimum that is not reached in any of these profiles (PES
> profile are shown in CG321_CG321_CG3C50_OG3C51.pdf), despite trying
> different combinations, as mentioned above, I also attempted a ±90° scan
> with a lower step size (10°), but the results are very similar.
>
> I find myself stuck in this situation. Could anyone provide advice or tips
> on this issue? Should I consider lowering the step size even further? I
> would greatly appreciate any guidance.
>
> PS: I'm using VMD 1.9.4 and ORCA 5.0.4.
>
> Best,
> Francesco
>
>
>
>
>
>