Page Comparison

Binding FE experiments with OpenFF 1.3 + GFN2XTB

• (Will upload slides here)

• JH – Tried to visualize trajectories to catch sampling issues.

  • DM – Rotamer sampling issues for rgroups?

  • (Needs to do more edges? How to do this?)

  • MB – Uses RDKit to make the MCSes.

  • DM – Could switch which mapping you get, and/or switch the coordinates of atoms

• DM – One thing I’m thinking about is that TYK2 is “the system where everything works”, so I’m wondering what we’d see on the other systems.

• LPW – An RMSE of 0.64 kcal/mol is really good. The parsley paper got around 1.0.

  • DC – Yeah, JChodera’s paper with ML FFs also showed about half a kcal per mol.

• JH – All the software is in place to run the whole JACS dataset, we’d just need more compute time.

• JH – It’s frequently not worth it to drive amide bonds. Not sure how to automate skipping this.

  • DM – It could be complex to figure out which ones to skip scanning

  • JH – I’m thinking of caching torsion parameters for all fragments from QCArchive, and distributing with software. This could play well with the caching functionality that I recently added.

  • SB – What’s the cost comparison between nromal FFs, XTB, and full QM?

    • JH – XTB is about 1 minute/fragment, full QM is hours. If you get clever with caching you can run the QM faster, but we haven’t incorporated that into bespokefit.

    • SB – Do we ever want to run full QM at this point? XTB seems plenty performant.

    • SB – PB, you’d experimented with XTB1 vs XTB2. What’s the tradeoff?

      • PB – On the set of our QM benchmark molecules (59 of them), wrt df-CCSD(T)/CBS//MP2-heavy-aug-cc-pVTZ baseline

        | Specification | RMSE in kcal/mol | MAE in kcal/mol |
        | gfn1xtb | 1.5271 | 1.0309 |
        | gfn2xtb | 1.2481 | 0.8554 |

      • JH – Orbnet paper compares GFN1 vs. 2. on torsionnet. GFN2 is a bit better, but it’s debatable whether it’s worth the cost.

      • LPW – Agree, it’s not clear how representative these plots are.

Bespokefit conda-force release

• JW – Bespokefit is now on conda -forge. Looking for an initial tester before we ship it to swope!

  • DC – I tried it yesterday and

    • I needed mamba to get it to install, is that a problem?

      • JW – I used to think it was, but I’m finding more and more that I need to do everything with mamba now. So I don’t think it’s that bad any more.

      • JH – Did you try to do psi4?

      • DC – No

      • SB – Current bespoke package doesn’t require psi4, targets toolkit-base to avoid AT/psi4 conflict. There was another dependency that had lots of pins, I talked to them and got that loosened up. I think it’s ready to send to Bill.

      • DC – Time to announce this to the world?

      • SB – Let’s get Bill to test it for a few days before we announce.

      • We’ll have Bill test bespokefit for 3 days, then JH will announce release.

    • It wasn’t clear to me how to have bespokefit use XTB instead of full QM.

      • SB – Agree – We need to document how to go through python to get XTB. We also need to add a commandline argument to get XTB.

      • JH – Agree, we’ll want to incorporate some pre-built commandline arguments.

• JW – Just made emergency bugfix release for OFF Toolkit, unfortunately an unrelated change broke forceblaance, which means it broke bespokefit. So we need to make a new FB release.

Overview of vsites and functional form work

• DC – Vsite work was started before we started with OpenFF.

• (base don https://chemrxiv.org/engage/chemrxiv/article-details/61c0d3a31e13eb80bb0010ec )(

• DC – sulfur lone pair vsites show good improvement

• DC – F-C bond charge vsite keeps falling inside the fluorine, with a positive charge

  • LPW – Would that basically be a sigma hole?

  • DC – It’s the opposite of what we’d expect for a sigma hole - The region that should be getting positive is instead becoming negative. But fluorine is said to see the least sigma hole effect.

• DC – Adding vsites reduces errors for densities and heats of vaporization

• DM – Is it accurate to say that, if someone were interested in working with this in the main OpenFF force fields, they could start with your placement of vsites?

  • MS – There are two questions for each vsite -

    • A discrete question of “should this vsite exist?”

    • Numerical questions of “what should the values be?”

  • MS – I know SB has infrastructure to do the fitting.

  • DM – So it seems like this is ready to start in OpenFF.

  • MS – Maybe, my student Yu-Tang may be able to start here, but he’s just beginning grad school so it’ll take a good amount of training.

  • MS – I think we need to pin down our electrostatics fitting procedure first. Will it be AM1, then fitting new BCCs? Without this we don’t have a foundation to begin fitting vsites.

• MS – Is there a heuristic to decide which vsites should exist?

  • DC – We only have a ~100 molecule set to help us decide, but these have informed us about where to put vsites. They largely indicate we need things like O and S lone pairs.

• CC – Which MD engine did you implement vsites in?

  • DC – OpenMM, using localcoordinatesite

  • CC – We might think about, at OpenFF, that we’re concerned about the ability to export to other engines…

  • (general – Support for our vsites in GROMACS is fine, but AMBER is unknown)

  • DM – I don’t think this should block our research. If we fit vsites that are good thenw e can push to get them implemented in engines.

• MS – If we agree that the goal of the study is to figure out which vsites SHOULD exist, then … Also figure out what the numbers should be.

• DC – We’ve experimented with replacing LJ potential with double-exponential.

• JH – Here are my fits with DExp - This is very preliminary! Mostly proof of concept to show that it could work.

• Image Added

• Original sage fit

Image Added

• Densities (normal on left, DExp on right)

Image Added

• JH – Some stuff with absolv, not finished yet

  • MS – I know how to fix that, can chat offline - Will send DC and JH a series of papers on it

  • DC – I’ll take a look at this before the ad board meeting

• MS – A few thoughts

  • it would be nice to jump from 2 to 3 parameters instead of 2 to 4 parameters

  • We want to get to the point where we can do bayesian inference on several different proposed functional forms (long term, 2 years). If you’re working along these lines it may be good to discuss this. But we basically need irrefutable evidence to convince people to switch funcitonal fomrs

  • Where this matters is pressure dependence. This will make a difference as we model the repulsive component. So with ions and high pressure systems.

• MS – To dos for me are

  • send papers to DC and JH

  • begin long-term planning for working together on improved nonbonded modeling.