AM1 restraint studies | @Connor Davel @Jeffrey Wagner @Owen Madin | CB: MD constrained, are bonds, valence angles changing/relaxing? Discussion topics 1. We want to stop proton rearrangements 2. when there are no proton rearrangements OE opt may be harmful, how bad is it? 3. We’re making a restraint scheme - What should our “gold standard” be for “doing it right”? CB: One universe says “there is a best set of AM1 charges for a certain geometry, and they are conformation dependent”. I don’t like this because strongly internally interacting structures make a mess of everything – Even when the conformers extend, they get stuck to water or protein contacts. Another universe says “One single set of charges is the best for every possible conformer of the molecule”. The evidence seems to indicate that we want the second option. So, the approach in part two of the talk (where you consider AmberTools AM1 as the “metric of success”) is only applicable to universe 1, and I don’t think that's the best way. Solvation energies and relative energies of conformers are good metrics of success So the thing you need to answer is “are really strong internal interactions allowable?” and I think that they’re not, since universe 2 is more important. If we use a more detailed QM method as a metric of success, then we need a way to keep those from having internal hbond rearrangement/strong interactions. You want a “redundant internal coordinate optimizer”, optimizing bonds and angles, but (con/re)strain torsions SB – GeomeTRIC offers this. CB – What really seems ideal is to let everything relax, as long as we don’t get “electrostatic collapse”, where we get strong internal electrostatics and hbonds.
CB – If you’re gonna use a fixed charge FF, you have to answer what the metric of success is. I used relative conformer energies and solvation free energies.
JW – Re: Comparing to conformer energies, we noticed that anywhere that AM1 would have had a proton transfer, then high-level QM would also have a proton transfer, How should we handle that? CB – The real problem isn’t proton transfer, it’s electrostatic collapse. That should be where the failure is considered to happen. So IF you consider this to be a failure, then this should be removed from the dataset altogether, or you should find some other way to “repel” away from those collapses.
JW – So, in conclusion it seems like, universe 2 is intuitively more fit for our needs than universe 1. Basically, we can’t define truth any better at this point without running high-level QM or hydration free energies. We also need to define whether electrostatic collapse is OK, or what it is. JW – Case of antechamber vs. quacpac disagreement – Should we report to OE? CB – It’s probably AM1 converging to a different electron distribution. But this is probably a super hard-to-fix thing, and it’s not clear whether it’s in our code or ambertools. Also this is one molecule out of 500, and we don’t know whether the downstream effects of this difference leads to a meaningful difference in relative energies.
CB – I outlined a restraint scheme to Simon a few months ago. It was basically “run a restrained opt, then run a full opt from the outcome of the restrained opt. Then see if the full opt has an electrostatic collapse, go back to the results of the restrained opt” SB – Agree. First catch proton rearrangements. Also, avoid electrostatic collapse. JW – These ideas sound good, but we’re limited by the speed of the geometric-antechamber integration
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Priorities/features/wishlist for Rosemary | @Christopher Bayly
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