Why energy value appear zero

[陳冠宇]

Dear sir,
I am a new one using gromacs and gmx_mmpbsa.
I found the interaction energy dramatically to appear zero in some frames after performing gmx_mmpbsa calculation.
Is it correct? or how can I fix the mistake?

Attached is my sharing of the mmpbsa.in script file, and output results.

I am looking forward to hearing from you soon.
Thank you

Sincerely,

Mark

***********************************

Mark, Guan-Yu Chen (陳冠宇) 

中國醫藥大學附設醫院 1JG1醫研部中醫藥研究發展中心

China Medicine Research and Development Center

China Medical University Hospital

Taiwan

Tel: +886-4-22053366 ext. 3316/5711

E-mail: markchen19822001(at)gmail.com 

E-mail: markchen19822001(at)yahoo.com.tw

祝 平安喜樂 ~ 福慧圓滿 ^^ 

注意：依據國家個人資料保護法規定,本信件及附加文件僅為傳遞於指定的收信人，且可能含有私人之專屬資料。如果您不是本通知的指定收信人，請立即自您的電腦系統刪除並通知本人，不得為任何之複製、使用或向第三人揭露，以免侵害他人權益，造成自身觸法，謝謝您的配合。

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[Mario Ernesto]

The results look fine to me... Please, check this section (https://valdes-tresanco-ms.github.io/gmx_MMPBSA/dev/output/) for more info on the output terms...

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[陳冠宇]

Dear sir,

Thank you for your reply.

Actually, I am confused about the results. 

For example,

When I estimate the binding energy during the trajectory starting from 1 to 30001 frames, the value of binding energy (GB+IE) is 37.9 kcal/mol (greater than 0 kcal/mol).

However, changed the trajectory starts from 15001 to 30001 frames, and the value of binding energy (GB+IE) is changed to -22.5 kcal/mol.

Whether different sampling has different binding energy is right or not?

It is confusing for me.

Subsequently, I check my trajectory (1~300 frames). I found that the delta energy (TOTAL) appears 0 kcal/mol during 9000 to 10000 frames. 

As attached, the trajectory suddenly appears at several dramatically higher peaks during 9000 to 10000 frames. Is it right? Could be shown on the manuscript for paper publication?

How should I process or choose the periods of the frames to define the correct binding energy?  

Looking forward to your reply.

Thank you

Mark

***********************************

Mark, Guan-Yu Chen (陳冠宇) 

中國醫藥大學附設醫院 1JG1醫研部中醫藥研究發展中心

China Medicine Research and Development Center

China Medical University Hospital

Taiwan

Tel: +886-4-22053366 ext. 3316/5711

E-mail: markchen19822001(at)gmail.com 

E-mail: markchen19822001(at)yahoo.com.tw

祝 平安喜樂 ~ 福慧圓滿 ^^ 

注意：依據國家個人資料保護法規定,本信件及附加文件僅為傳遞於指定的收信人，且可能含有私人之專屬資料。如果您不是本通知的指定收信人，請立即自您的電腦系統刪除並通知本人，不得為任何之複製、使用或向第三人揭露，以免侵害他人權益，造成自身觸法，謝謝您的配合。

IMPORTANT NOTICE OF DISCLAIMER
The information in this e-mail and any attachments is intended only for the person or entity to which it is addressed and may contain confidential and/or privileged material. Any review, retransmission, dissemination or other use of, or taking of any action in reliance upon, this information by persons or entities other than the intended recipient is prohibited. If you are not an intended recipient, please delete the message and any attachments and notify the sender of misdelivery.

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Mario Ernesto <marioe...@gmail.com> 於 2022年8月30日 週二 下午5:51寫道：

[Mario Ernesto]

Overall it looks fine, excepting those peaks between 8000th and 12000th frames... is your trajectory fitted and with the PBC removed?

https://valdes-tresanco-ms.github.io/gmx_MMPBSA/dev/Q%26A/calculations/#possible-solutions

[陳冠宇]

Dear sir,

Thank you for your reply.

After gromacs running, I do some steps like this as below: 

   1. Generate a group that contains both molecules
   2. remove the PBC
   3. remove the rotation and translation with respect to the reference structure (optional)

https://valdes-tresanco-ms.github.io/gmx_MMPBSA/dev/gmx_MMPBSA_running/

Therefore, index.ndx and md_0_300_noPBCfit.xtc were obtained from above steps and subsequently were set as one of parameters for gmx_mmpbsa running.

   $mpirun -np 30 gmx_MMPBSA MPI -O -i mmpbsa.in -cs md_0_300.tpr -ci index.ndx -cg 1 19 -ct md_0_300_noPBCfit.xtc -cp topol.top -o FINAL_RESULTS_MMPBSA.dat -do FINAL_DECOMP_MMPBSA.dat -eo FINAL_RESULTS_MMPBSA.csv -deo FINAL_ENERGY_RESIDUE.csv -nogui

The program can be execulated. gmx_MMGBSA run.

Besite, I also run the program like this step:  

   #gmx editconf -f md.tpr -o md.pdb

in order to generate the structure from tpr file, like this:
   $gmx editconf -f md_0_300.tpr -o md_0_300_H295complex.pdb

However, if I added the md_0_300_H295complex.pdb into the command line, like this :

   $mpirun -np 30 gmx_MMPBSA MPI -O -i mmpbsa.in -cs md_0_300.tpr -ci index.ndx -cg 1 19 -ct md_0_300_noPBCfit.xtc -cp topol.top -lm ftwoninefive_bcc_gaff.mol2 -cr md_0_300_H295complex.pdb -o FINAL_RESULTS_MMPBSA.dat -do FINAL_DECOMP_MMPBSA.dat -eo FINAL_RESULTS_MMPBSA.csv -deo FINAL_ENERGY_RESIDUE.csv -nogui

It can not run. The program would be terminated. The error that protein does not match was shown.

How can I re-check and fix my trajectory or other files?

Does this mean my trajectory is without fitted well and the PBC without being removed okay? 

I am looking forward to hearing from you soon.

Thank you

Sincerely,

Mark

***********************************

Mark, Guan-Yu Chen (陳冠宇) 

中國醫藥大學附設醫院 1JG1醫研部中醫藥研究發展中心

China Medicine Research and Development Center

China Medical University Hospital

Taiwan

Tel: +886-4-22053366 ext. 3316/5711

E-mail: markchen19822001(at)gmail.com 

E-mail: markchen19822001(at)yahoo.com.tw

祝 平安喜樂 ~ 福慧圓滿 ^^ 

注意：依據國家個人資料保護法規定,本信件及附加文件僅為傳遞於指定的收信人，且可能含有私人之專屬資料。如果您不是本通知的指定收信人，請立即自您的電腦系統刪除並通知本人，不得為任何之複製、使用或向第三人揭露，以免侵害他人權益，造成自身觸法，謝謝您的配合。

IMPORTANT NOTICE OF DISCLAIMER
The information in this e-mail and any attachments is intended only for the person or entity to which it is addressed and may contain confidential and/or privileged material. Any review, retransmission, dissemination or other use of, or taking of any action in reliance upon, this information by persons or entities other than the intended recipient is prohibited. If you are not an intended recipient, please delete the message and any attachments and notify the sender of misdelivery.

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Mario Ernesto <marioe...@gmail.com> 於 2022年8月30日 週二 晚上9:04寫道：

[Mario Ernesto]

You can check the trajectory in VMD and check if it is fine on the frames where you see the peaks... Probably, PBC hasn't been properly removed in those...

[陳冠宇]

Dear Sir,
Thank you for your suggestion, I will check it by VMD tomorrow.
I hope I can solve this mistake.

May I ask if I found it is not fine or does not fit well in trajectory frames, how can I do it?
About PBD removal,
Does it also find in VMD?
Does remove PBD using the same command again?

Looking forward to hearing from you soon.
Thank you

Sincerely,

Mark

***********************************

Mark, Guan-Yu Chen (陳冠宇) 

中國醫藥大學附設醫院 1JG1醫研部中醫藥研究發展中心

China Medicine Research and Development Center

China Medical University Hospital

Taiwan

Tel: +886-4-22053366 ext. 3316/5711

E-mail: markchen19822001(at)gmail.com 

E-mail: markchen19822001(at)yahoo.com.tw

祝 平安喜樂 ~ 福慧圓滿 ^^ 

注意：依據國家個人資料保護法規定,本信件及附加文件僅為傳遞於指定的收信人，且可能含有私人之專屬資料。如果您不是本通知的指定收信人，請立即自您的電腦系統刪除並通知本人，不得為任何之複製、使用或向第三人揭露，以免侵害他人權益，造成自身觸法，謝謝您的配合。

IMPORTANT NOTICE OF DISCLAIMER
The information in this e-mail and any attachments is intended only for the person or entity to which it is addressed and may contain confidential and/or privileged material. Any review, retransmission, dissemination or other use of, or taking of any action in reliance upon, this information by persons or entities other than the intended recipient is prohibited. If you are not an intended recipient, please delete the message and any attachments and notify the sender of misdelivery.

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Mario Ernesto <marioe...@gmail.com> 於 2022年8月30日 週二 晚上10:01寫道：

[Mario Ernesto]

your energy looks stable after the 12000th frame... you can consider the previous frames as equilibration and that way don't have to bother too much with the wrong frames...

[陳冠宇]

Dear Sir,

Can I only estimate the Enthalpy energy from the last 10 ns?

Can I estimate the IE (entropy) with 100% segments from the last 10ns?

Can I combine the above energy (enthalpy+entropy) as gibbs free energy to estimate the binding ability between ligand and protein?

I am looking forward to hearing from you

Thank you

Sincerely,

Mark

***********************************

Mark, Guan-Yu Chen (陳冠宇) 

中國醫藥大學附設醫院 1JG1醫研部中醫藥研究發展中心

China Medicine Research and Development Center

China Medical University Hospital

Taiwan

Tel: +886-4-22053366 ext. 3316/5711

E-mail: markchen19822001(at)gmail.com 

E-mail: markchen19822001(at)yahoo.com.tw

祝 平安喜樂 ~ 福慧圓滿 ^^ 

注意：依據國家個人資料保護法規定,本信件及附加文件僅為傳遞於指定的收信人，且可能含有私人之專屬資料。如果您不是本通知的指定收信人，請立即自您的電腦系統刪除並通知本人，不得為任何之複製、使用或向第三人揭露，以免侵害他人權益，造成自身觸法，謝謝您的配合。

IMPORTANT NOTICE OF DISCLAIMER
The information in this e-mail and any attachments is intended only for the person or entity to which it is addressed and may contain confidential and/or privileged material. Any review, retransmission, dissemination or other use of, or taking of any action in reliance upon, this information by persons or entities other than the intended recipient is prohibited. If you are not an intended recipient, please delete the message and any attachments and notify the sender of misdelivery.

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Mario Ernesto <marioe...@gmail.com> 於 2022年8月30日 週二 晚上10:43寫道：

[Mario Sergio Valdes]

Can I only estimate the Enthalpy energy from the last 10 ns?

Yes. There are several studies showing that better results are obtained by combining several short trajectories rather than one very long one.

 

Can I estimate the IE (entropy) with 100% segments from the last 10ns?

In the computation of the IE, convergence is very important, so we automatically define that the average will be computed only in the last quartile (ie_segment=25) of the defined trajectory. In your case, the internal energy (ΔGgas) standard deviation value is almost 5 times higher than the value considered as reliable (check the output file warning). If you look at the IE plot using gmx_MMPBSA_ana you can see that it is cumulative, so using 100% of the trajectory is not recommended.

 

Can I combine the above energy (enthalpy+entropy) as gibbs free energy to estimate the binding ability between ligand and protein?

Yes. Note that the IE calculation has specific conditions and that these methods (GB, PB, etc) can overestimate the energy, being good for comparing similar systems, e.g. set of ligands against the same target. 

 

[陳冠宇]

Dear Sir,
Thank you for your previous suggestion.
I think the mistake has been solved. I found that the mistakes appeared during removIng the PBC and fitting the structure.
As the results are attached, the motive behaviors of ligand binding to protein during the 30001 frames are stable and the values of binding interaction energies are negative.  

I would like to further ask some questions.

1. In this job, I set igb=8 and PBRadii = 4 which replies to the literature, https://www.frontiersin.org/articles/10.3389/fmolb.2021.646524/full. Does it be suitable to estimate ligand-protein binding free energy calculations and decomposition energy?
2. At this same time, I also perform the decomposition analysis. I found the results show three categories, including "TDC", "SDC", and "BDC". In each category, different kinds and amounts of residues were shown. Additionally, the results in TDC which is not only showed the energy of residues but also showed the energy of "ligand". How can I explain those data?
3. How many frames (default) to estimate the data of "Mov. Av." (moving average ?) in energy trajectory?
4. Is it right about the energy of Gsolv is positive (>0)?
5. How to explain the data of interaction entropy, especially "ie" vs "sigma"?

Looking forward to hearing from you soon.
Thank you

Sincerely,

Mark

 

***********************************

Mark, Guan-Yu Chen (陳冠宇) 

中國醫藥大學附設醫院 1JG1醫研部中醫藥研究發展中心

China Medicine Research and Development Center

China Medical University Hospital

Taiwan

Tel: +886-4-22053366 ext. 3316/5711

E-mail: markchen19822001(at)gmail.com 

E-mail: markchen19822001(at)yahoo.com.tw

祝 平安喜樂 ~ 福慧圓滿 ^^ 

注意：依據國家個人資料保護法規定,本信件及附加文件僅為傳遞於指定的收信人，且可能含有私人之專屬資料。如果您不是本通知的指定收信人，請立即自您的電腦系統刪除並通知本人，不得為任何之複製、使用或向第三人揭露，以免侵害他人權益，造成自身觸法，謝謝您的配合。

IMPORTANT NOTICE OF DISCLAIMER
The information in this e-mail and any attachments is intended only for the person or entity to which it is addressed and may contain confidential and/or privileged material. Any review, retransmission, dissemination or other use of, or taking of any action in reliance upon, this information by persons or entities other than the intended recipient is prohibited. If you are not an intended recipient, please delete the message and any attachments and notify the sender of misdelivery.

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Mario Sergio Valdes <mariosergi...@gmail.com> 於 2022年8月30日 週二 晚上11:26寫道：

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[marioe911116]

1. In this job, I set igb=8 and PBRadii = 4 which replies to the literature, https://www.frontiersin.org/articles/10.3389/fmolb.2021.646524/full. Does it be suitable to estimate ligand-protein binding free energy calculations and decomposition energy?

        -igb8 contains more parameters than the previous versions (ibg2 and 5) and should give you more reliable estimates of solvation energy

1. At this same time, I also perform the decomposition analysis. I found the results show three categories, including "TDC", "SDC", and "BDC". In each category, different kinds and amounts of residues were shown. Additionally, the results in TDC which is not only showed the energy of residues but also showed the energy of "ligand". How can I explain those data?

        TDC is total decomposition (total energy)

        SDC is side chain decomposition (side chain energy)

        BDC backbone decomposition (backbone energy)

1. How many frames (default) to estimate the data of "Mov. Av." (moving average ?) in energy trajectory?

        usually, 1000 frames should be enough to get a decent estimate

1. Is it right about the energy of Gsolv is positive (>0)?

        energy to desolvate groups, this process consumes energy, especially if there are polar groups involved

1. How to explain the data of interaction entropy, especially "ie" vs "sigma"?

        sigma is the standard deviation of the interaction energy... it has been proven that sigmas greater than 3.6 kcal/mol (~15 kJ/mol) give unreliable values for the interaction entropy... check this paper for more info       (https://doi.org/10.1021/acs.jctc.1c00374)

hope this helps!