Re: [GaMD-discuss] Kinetic analysis from LiGAMD results

[Miao, Y. <Yin...@me...>]

Hi Qianwei,


  1.
How to find the frequencies (wm and wb) and free energy barrier (delta F) for binding, unbinding, and barrier?  Taking the q4MD-Aspirin system as an example, there is multiple energy minimum and maximin based on the 1D PMF plot. The delta F of unbinding ("off") seems to be the first peak value in Figure 4c (matching the 4 kcal/mol in Table S2). But the binding delta F does not match with the first minimum on the plot. Similar to the frequencies calculation, while it is from the second derivatives of F(A), but I don't understand at what distances.

The binding delta F should be F (barrier at 6.5 Angstrom) - F (unbound minimum at 19.5 Angstrom) = 4.00079-3.03217.
wm and wb are the second derivatives of PMF at energy minimum and barrier, respectively.



  1.
Assuming I have the frequencies and delta F, I will have all numbers to find the "rate of a chemical reaction" to determine the acceleration. Then what's next to find the kon and koff from the simulation? I don't understand the description "The resulting numbers are then plugged into eq 11 to estimate accelerations of the ligand binding and dissociation rates during LiGaMD simulations (Appendix C), (26) which allows us to recover the original kinetic rate constants." in the method section.

You can calculate the accelerated rates kon* and koff* directly from the simulations according to the ligand unbound and bound time periods. Once you figure out the acceleration factors, you can divide the accelerated rates by these factors to recover the original kinetic rates.

Hope this helps,
Yinglong


Yinglong Miao, Ph.D.
Associate Professor
Department of Pharmacology and
Computational Medicine Program
University of North Carolina - Chapel Hill
Tel: 1-919-962-5696
http://miaolab.org

Editor-in-Chief
npj Drug Discovery
https://www.nature.com/npjdrugdiscov

On Oct 22, 2025, at 5:20 PM, Li, Joyce via GaMD-discuss <gam...@li...> wrote:

Hello community,

I'm trying to recover the original kinetic rate constants as mentioned in the LiGAMD and LiGAMD2 paper. While testing on the example (the LiGAMD for q4MD-Aspirin system), I can follow the steps to find the apparent diffusion coefficient D (as well as the friction constant) using the 1D PMF data and the smol solver. But I get stuck in the following steps.

  1.
How to find the frequencies (wm and wb) and free energy barrier (delta F) for binding, unbinding, and barrier?  Taking the q4MD-Aspirin system as an example, there is multiple energy minimum and maximin based on the 1D PMF plot. The delta F of unbinding ("off") seems to be the first peak value in Figure 4c (matching the 4 kcal/mol in Table S2). But the binding delta F does not match with the first minimum on the plot. Similar to the frequencies calculation, while it is from the second derivatives of F(A), but I don't understand at what distances.


  1.
Assuming I have the frequencies and delta F, I will have all numbers to find the "rate of a chemical reaction" to determine the acceleration. Then what's next to find the kon and koff from the simulation? I don't understand the description "The resulting numbers are then plugged into eq 11 to estimate accelerations of the ligand binding and dissociation rates during LiGaMD simulations (Appendix C), (26) which allows us to recover the original kinetic rate constants." in the method section.

Thank you!

Best,
Qianwei
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