Free energy computation for Protein-protein/peptide complex

[HrishiDhondge]

Hello all,
I am looking for some protocols to perform free energy computation for the protein-protein or protein-peptide complex. There are no tutorials for this in the alchemiscale repository. It isn't mentioned anywhere if it is a suitable task for this tool.
Can we use this repo for the computation of relative binding free energies for a protein-protein or protein-peptide complex? If yes, are there any resources available that can be followed?

[dotsdl]

Hi @HrishiDhondge, thanks for asking!

Do you mean to calculate the binding free energy of two (or more) proteins in complex with each other? This is usually outside of the domain of applicability of "alchemical" methods, and may require an incredibly high degree of sampling AFAIK.

I may be misunderstanding your meaning though! Any details you can share can help us answer more clearly whether alchemiscale is appropriate or not.

[HrishiDhondge]

Hey @dotsdl,
Thanks for the prompt response.
Indeed, I meant to compute the binding free energy of two or more proteins in a complex. I am also interested to compute the binding free energy of a protein-peptide complex.
Do you think this can be achieved with alchemiscale via longer simulations?
Thanks in advance!

[dotsdl]

No problem, happy to discuss!

Alchemical methods for calculating free energies rely on being able to get sufficient sampling of interactions, which can be challenging even for a small molecule interacting within a binding pocket of a (often much larger) protein. I'm not aware of folks using these methods for protein-protein interactions, but this may be lack of knowledge on my part.

@IAlibay, @hannahbaumann, @jthorton, @JenkeScheen: any thoughts on this topic from a science methods perspective?