2023-05-04 Protein FF meeting note

Peptide and GB3 benchmarks in OPC water

Chapin Cavender

• Slides will be uploaded

• Meeting is recorded

• Slide 7: error bar is confidence interval that comes from standard error

  • DLM – evidence seems to support need for us to co-optimise our own water model

• Slide 8: aside from Val3, OPC generally improves results for SMIRNOFF

• Slide 9:

  • MS: SMIRNOFF RMSDs in GB3 look higher than 14SB

    • CC: they are slightly (2.0 vs 1.7), but not clear to me that’s a problem

• Slide 10:

  • CC: no unfolding yet at 3 us – in TIP3P these unfolded at 2 us, so cautiously optimistic

    • MS: points out that one replicate is going up a bit in RMSD

    • CC: we’ll run it for longer

• WS: this looks great. TIP3P has an unrealistically large diffusion constant – I’ll bet OPC is much closer to experiment, so maybe kinetics are slower, so anything crazy might take longer to happen

  • MS: confirms diffusion constant is lower

• LPW: what are you looking at?

  • CC: I’m looking at scalar couplings:

    • 3-bond Karplus

    • interresidue scalar coupling between amide NH to C=O of another. On Slide 12 I’m showing backbone dihedrals (1-3), side-chain dihedrals (3-6), last is inter-residue H-bond

    • LPW: I’ve done these with RMSEs in hertz. I haven’t done chi squared, and I don’t know how to convert to RMSE, so I’m not sure how to compare our results. (shares results)

    • CC: I should be able to convert my chi2 values into RMSE but I don’t know the number off the top of my head

    • LPW: I’m curious about the spread of values – high chi2 suggests to me that it is, but my results should have a chi2 of <= 1

    • MS: is the question here if the J-couplings differences are small as you’d expect?

    • BS: you showed experimental values

    • CC: the number I’m using for exp uncertainty is the RMSE between parameterised Karplus couplings and what they use to do the parameterisations… they’re generally around 0.25-0.6 hz. This also depends on which set of Karplus eqns or coefficients you use. The BBs have multiple options. Do you recall what you used LPW?

    • LPW – it’s in the paper, not quite sure now (paper from 2017). (checks paper) I’m using Boister and Backs (? spelling) which should have RMSEs between 0.6 and 1

    • CC – I’m using Backs and Gelli (? )

• CC: recommend using OPC from now on

  • MS: what about tip4p-fb and other four-point models? Others may also balk at extra computational cost

  • CC: good point

  • MS: want to do subset of mixture properties with a bunch of water models. OM is gone, LW has other work to do, maybe I can find someone in my group to do it. e.g. Anika

  • BS: agree that’s a great idea

  • MS: enthalpies of mixing, densities that involve water, transfer solvation energies. Maybe can coordinate with LW to see how much there is to do. MS and Lily can coordinate

  • CC: can repeat with tip4p-fb since we already have the port in SMIRNOFF

  • LPW: the parameters between OPC and TIP4P-FB are very different. Similarly, OPC3 vs TIP3P-FB are very similar.

  • LPW: could see if you could reproduce tipxp-fb in evaluator with tipxp data set, then add mixture properties

  • MS: I think we can test water models before we re-fit models

  • JW: wrt virtual sites, OpenFE may not have infrastructure to roll out virtual sites for a while. We may not be able to easily do FE calcs with four-site models.

  • CC: we thought we would wait until release candidate to do protein-ligand benchmarks, which will be when I hand off to Lily for refit

  • MS: we don’t want to do PLBs until we are comfortable about protein stability

  • JW: i’ll keep them up to date and ask when they may have vsites implemented

  • BS: I thought OpenFE discussion was to do with vsites on ligands, not water model

  • JW: I think water model might be a bit simpler. In my understanding, the difficulty is with alchemical transformation bookkeeping.

  • MS: if vsite has no charge on it, the statistical mechanics are identical as if there’s no vsite

  • DLM: from OpenMM POV, it should just be a matter of running with the water model, whichever one it is. Unless they’ve done something really weird, it should be quite simple

  • MS: since water model isn’t changing, yes, it should be fairly simple

  • BS: agree

  • JW: I’m just being cautious in case OpenFE can’t handle it

  • DLM: worth putting on their radar

  • (general agreement 4-site water should be straightforward)

• CC: summarise to do:

  • Run benchmarks with tip4p-fb

  • MS will see if someone can run small molecule properties

    • MS: won’t be before OpenFF meeting, so let’s nail the plans down at the meeting in a week. We can aim for results at end of May. Maybe Tim could do it

    • CC: we can use these results to decide further protein benchmarks

    • DLM: can use agenda on Monday to figure this out

  • MS will sync up with Lily to figure out what properties to use

  • CC will sync up with LPW about couplings

• Update on AF:

  • She’s expanding dataset to look at more protein systems

  • CC – I’ll continue running other water models and new observables for folded proteins

• MS: on Monday is when we have updated NIH information

  • MS: we can put a list of accepted publications. Anything that’s been accepted in the past two months?

    • Sage

    • Owen’s surrogate model

  • MS: covid regulations still in place, so we can submit up to 1 page of preliminary data

    • Since our results are middling, not sure this is the best idea. Should we try to show tentative results?

      • DLM: I don’t think I’ve ever submitted anything

    • Consensus: don’t submit tentative results

• CC: thanks JW and MT for helping with OPC!

• MT: TIP4P (EW and FB variants) are not in the forcefields repo but the work is done, just needs a review/merge/release when that’s important