Include custom restraints in the Relative Free Energy Protocol

[PabloNA97]

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Lately, I've been working with some proteins that are missing several large loops, which I believe are causing instabilities during the simulation [1].

Of course, one possible solution would be to model the missing loops. But I'm wondering how difficult it would be to include custom restraints in the terminal residues for cases where loops are very large or they are far from the binding site.

I haven't seen any information on this in previous issues or the documentation, but if I missed it and you could point me in the right direction, that would be very helpful.

[1] For this protein I mentioned, I was finding the infamous Potential energy is NaN error for some edges:

...
ERROR:openmmtools.mcmc:Potential energy is NaN after 19 attempts of integration with move LangevinDynamicsMove Trying to reinitialize Context as a last-resort restart attempt...
ERROR:openmmtools.mcmc:Potential energy is NaN after 20 attempts of integration with move LangevinDynamicsMove
...

I checked the ligands alignment and mapping, the forcefield_settings.hydrogen_mass setting, run plain MD at the end points, increased equilibration length, changed the small molecule FF and finally checked the forces per particle in the nan-error-logs (I didn't try reducing the timestep, as the system is big and already runs slowly). I couldn't get rid of the error but found that the atoms experiencing the largest forces (300 times larger than the average force per particle) were consistently located in the terminal residues of the unmodeled missing loops.

[IAlibay]

Hi @PabloNA97,

Apologies for the slow response. Unfortunately adding custom restraints isn't something that is possible with the OpenFE RBFE Protocol, however it is something that we have been considering for a while.

There are lots of different ways these types of restraints could be implemented, could you maybe give us some insights into the types of restraints you would want to use? Is this mostly backbone RMSD restraints? Or some kind of distance restraint between C-alpha atoms of different residues?

[PabloNA97]

Hi @IAlibay,

Don't worry, thank you for taking the time to answer :)

I would use RMSD restraints on C-alpha positions, to limit the flexibility of regions with unmodeled loops.

[Kamecs]

Hi @IAlibay

I also mention my opinion to this thread.

In my calculations of membrane proteins, I would like to calculate membrane proteins stably without stretching the membrane by keeping the CA atoms of the protein spring-constrained. Additionally, the same restraint is required to calculate a portion of the structure of a large protein. To do these, I need a scheme to constrain specified atoms.

Best regard.