High interaction energy standard deviation warning in protein-protein binding free energy calculation

[jay Pang]

Dear sir,

I have selected a stable frames (last 50ns) to calculate protein-protein interactions using gmx_MMPBSA, however, there is a high interaction energy standard deviation warning and positive energy is gained,I would like to ask for your help with the following：
1.Based on the RMSD graph, is my method reliable?
2.How to adjust to get reasonable results？

[marioe911116]

Even the slightest variations in interaction energy could contribute to a non-converged interaction entropy. Check the entropy section in the docs:

https://valdes-tresanco-ms.github.io/gmx_MMPBSA/dev/input_file/#entropy-options

especially this paper about the drawbacks of the interaction entropy method:

https://pubs.acs.org/doi/full/10.1021/acs.jctc.1c00374

[jay Pang]

Thanks for your help.Since it is difficult to calculate reliable interaction entropies from MD trajectories (with large standard deviations, regardless of whether the IE or C2 method is used), is it possible to use interaction energies to indicate that two proteins in a protein-protein system are interacting and binding?
Or are there other methods that can be used to determine the interaction and binding of these two proteins?

[marioe911116]

MMPB(GB)SA method is typically useful in relative comparisons context and not that much for absolute calculations. A negative value is certainly a good indication, although is not definitive if you don't have any experimental data to validate it. Per-residue decomposition analyses are usually good in these cases to determine which residues contribute the most to the binding energy.

[jay Pang]

thanks,  should I perform per-residue decomposition analyses similar to the following :
https://valdes-tresanco-ms.github.io/gmx_MMPBSA/dev/examples/Decomposition_analysis/

[Mario E. Valdes-Tresanco]

Yes

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