2020-12-02 BespokeFit meeting notes

TYK2 Refit validation

• TYK2 Refit Validation

• (General) GAFF performs really well here. What specifically is it doing well?

  • (General) – Bond and angle terms?

  • DM – We haven’t done hessian-based fitting. That could help a lot. Also using optimization trajectories. Also using high-temperature MD is likely to stress bond and angle geometries a lot.

  • DC – Interesting that GAFF is doing better against OUR QM data than we are.

  • JH – Agree that using optimization trajectories should improve the quality of these fits. I think the torsions here are nearly perfect – I doubt that we can improve any more without refitting bonds and angles.

• DM – we should try to fit to the optimization trajectories

  • JH – will try.

• DM: Try to modify the k values for the bonds/angles; use existing parameters

• DR – Do you minimize snapshots from MD before getting MM and QM energies?

  • JH – No minimization

  • DR – IIRC, normal mode sampling was used to generate confs for ANI (maybe with minimization in the middle)

  • DC – We’re using a lot of ANI for our methods, generating confs using up to 1000K, seeing good agreement between ANI and QM energies.

  • DR – mol size?

  • DC – Small fragments

• JW – what FF was used for the high temperature MD

  • JH – 1.0.0

  • JW – this might bias the conformations generated. Maybe we should use something like UFF instead to compare with oFF and GAFF

  • DM – GAFF might also be doing the same

  • JW – doing minimized conformers would remove bias, but maybe expensive

• DM – how quick can you generate these plots?

  • JH – about 3000 single-points/day

  • Should I try doing the MD with ANI instead?

    • DM – pursue it if experiments won’t take much time

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Comparison of ANI-2x energies and QM

• ANI2X comparison to QM energy looks better, but there is an issue with convergence

  • DC – What’s the status of issues with ANI torsiondrives?

  • JH – Complicated. They’re retraining it.

  • JW – What was the problem with this?

  • DR – The CELU function in one layer of their network led to nonsmooth second derivatives, which choked geomeTRIC up.