Add WP6 submissions

[davidlmobley]

No description provided.

[procacci]

My feelings on this, future (bCDs), and on past (CB8) host-guest
challenges are that the focus is too much on force fields while being
somehow unfaithful to the original commitment of the challenge. In my
understanding, that commitment was aimed at identifying the most
appropriate methodology in dealing with the SAMPLing of systems with
disparate time scales/complex collective variables and hence in
producing sufficiently reliable (and reproducible) binding free
energies. WP6 is a mostly rigid host that does not involve any
serious sampling issue. The very same can be said for the guest
molecules. This is at variance with the reality of ligand-protein
systems where both the host (the binding pocket) and the guest
(drug-like compounds with up to 9 rotatable bonds) are characterized
by a complex conformational landscape. Besides, the issue of the
protonation state of heavily charged WP6 is an extra complication that
can affect severely the prediction. If WP6 is in part protonated at ph
7.4, then the BFEs of the guest cations (12 out of 13) computed
assuming a fully deprotonated state for WP6 are expected to be
overestimated. On top of all this, electrostatic interactions have
certainly a prevailing role in shaping the affinity. So, despite all
these modelization challenges, it was quite a surprise for me to see
that all the MD-based methodologies performed decently, whether they
used openFF GAFF or AMOEBA.

I do think that testing FF is important but I also think that the
SAMPLing issue in BFE determination is still far from being solved for
protein-ligand systems, even in the GPU era. My hope is that in the
future challenges these two crucial issues (FF and SAMPLing) are
addressed in separate specialized sessions: i) test the FF (and any
other physical methods) for rigid host and guest challenges ii) test
MD-based methodologies for protein-ligand systems, requesting for all
participants to use only one (well-established) FF. The common set of
topological/parameter files for the most popular MD codes could be
provided by the organizers with little work.

Using a fancy and expensive FF (e.g. AMOEBA or QM-M) with a poor
sampling methodology in a system where sampling is important makes no
real sense in my view. By the same token, using a fancy sampling
methodology with a poor FF in systems where sampling is not an issue
makes no sense as well. I am quite convinced that disentangling the FF
issue (systematic errors) from the sampling issue (reproducibility)
will allow us to move forward more quickly.

Piero Procacci

[davidlmobley]

I'm going to migrate your comment to the issue tracker as I'll certainly lose it here on this pull request. Stay tuned for a comment there.