2023-04-06 Protein FF meeting note

General updates

• JW – Expect OFFTK 0.13 soon, with support for loading multicomponent PDBs (proteins+waters+monoatomic ions+small molecules)

GB3 benchmark simulations

Chapin Cavender

• CC will link slides here

• JW – So, slide 37 is showing there’s a kinda barrier “added” in ff14sb that might prevent transitions over phi=180?

  • CC – Yeah, that’s a place where there’s a barrier, but remember that this is periodic so this can wrap around.

• MS – Does it look like we have stabler alpha helices?

  • … – Hard to tell, more analysis needed.

  • MG – It’s possible that our hbonding energies are different. Could do gas phase calcs to see

• “slide 52"

  • JW – Hard to tell what’s up here - There’s so little alpha helix propensity in the 3-mers that it’s difficult to figure out

  • MG –

  • CC – Could study sidechain rotamers more , instead of just phi and psi

  • CC – Could also look at tau angle - Some xtal structure info on that

  • MG – If you look at GB sims where helix partly unfolds, is there an initiating event that we can identify? Like the helix pulling away from the backbone or something?

    • CC – I don’t see anything by eye, but I’m thinking of checking out the tau or omega angles.

    • JW – Maybe something with ions?

    • CC – Using the same ion params for all, there’s just 2ish ions in the box to match experiment conditions

  • JW – Also re: previous comments that maybe our hbonds are too weak, we’re seeing that beta sheets are increasing while we’re losing alpha helices

    • CC – Yeah, I think checking the other angles could help here.

  • CC –

    • MG – Could be a good idea to go ahead to alpha helical peptide sims,

  • CC – What additional experiments should I prioritize with my time?Currently first priority is alpha helical sims, the sidechain analysys for existing sims, then hbonds in existing sims and maybe in gas phase dimers, and priority 4 is tau angle.

  • MS – This is a good proof that the benchmarks suggested in the paper are good

  • PB – How are the force constants here?

    • CC – Some periodicities have ks over 5kcal/mol, but that’s also true for ff14sb

    • PB – The impropers might be a contributor to the error here

    • CC – Do you think the impropers might have k values that are too large?

    • PB – Yeah, maybe. One improper changed a lot from the previous values we were using - (i4, not changed in openff-2.0.0, but refit in Chapin’s starting point FF)?

      • CC – Has a value of 1.2 kcal/mol

    • JW – The nitrogen centered improper may be i6?

  • MS – This has shown that, even if we get everything right that we intend to get right, it might go wrong for other reasons. So this could be a good reason to expand our validation set… replica exchange?

    • CC – Maybe melting temps/helix propensity vs. temp?

    • MS – Given how GB3 didn’t work even though QM fits looked good, J couplings look right, we might need a larger validation set. This will head off our future users reporting issues after release.

    • CC – That’s how I’m thinking about this as well - Would like to get to the bottom of GB3, and find a way to assess that sort of problem more directly.

  • JW – Could the energy surface difference be due to different QM reference data?

    • CC – Amber used MP2 (which is widely considered to do dispersion correcitons better than our basis+method). But IIRC PB found that our results are very close to MP2 with dispersion.

    • PB – Yeah, my analysis found that we’re very comparable in terms of QM methods.

    • CC – Notably, in ff19sb, they used a DFT model in implicit solvent.

    • MS – So there may be some differences, but it seems likely.

• CC – There’s also a difference in how the fitting is done - CSimmerling fits to conformers in a different way than we do, which is kinda what Swope suggested. But our fitting infrastructure would need fundamental changes to do this.

  • MS – Could be good to look at those metrics

  • CC – Will do.