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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. 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.
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Bespokefit conda-force release | JW – Bespokefit is now on conda -forge. Looking for an initial tester before we ship it to swope! 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.
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Overview of vsites and functional form work | DC – Vsite work was started before we started with OpenFF. (base don Exploration and Validation of Force Field Design Protocols through QM-to-MM Mapping )( 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 - 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? 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. Original sage fit
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