VMD-L Mailing List

From: Klimkowski, V (vklimkow_at_butler.edu)
Date: Thu Mar 14 2024 - 18:23:27 CDT

  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!75ddZo8QX7EVn6zrA7P2JBEkFm2UeLil_UeNhfEjs77RvttZmVJ3UDi4K0y3POrYAHMR1n7EAtok-npjzIwqUw$
  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://static-content.springer.com/image/art*3A10.1007*2Fs10822-022-00464-3/MediaObjects/10822_2022_464_Fig1_HTML.png__;JSU!!DZ3fjg!75ddZo8QX7EVn6zrA7P2JBEkFm2UeLil_UeNhfEjs77RvttZmVJ3UDi4K0y3POrYAHMR1n7EAtok-nqG_RmaEg$ ]<https://urldefense.com/v3/__https://doi.org/10.1007/s10822-022-00464-3__;!!DZ3fjg!75ddZo8QX7EVn6zrA7P2JBEkFm2UeLil_UeNhfEjs77RvttZmVJ3UDi4K0y3POrYAHMR1n7EAtok-npjzIwqUw$ >
On the force field optimisation of $$\\beta$$ -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!75ddZo8QX7EVn6zrA7P2JBEkFm2UeLil_UeNhfEjs77RvttZmVJ3UDi4K0y3POrYAHMR1n7EAtok-npjzIwqUw$ >
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 $$\\beta$$ -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 thats 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<mailto: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<mailto:gumbart_at_physics.gatech.edu>> ha scritto:
Indeed, its 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<mailto: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 escribi:

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