MC states not mixing in 0.16

For nearly the same experiment (only difference is slight change in clearance and existence of switch_distance), MC states seem to not mix in 0.16, while it seems to work in 0.15 (see attached YAML files)–i doubt these differences contribute to the overall result though. yank_mc.zip

During yank analyze in 0.15, the reported state mixing matrix is (relatively) populated (see attached JQ1_15_analyze.out), while in 0.16, it is completely empty (see attached JQ1_16_analyze.out). Furthermore, the following is also reported in 0.16:

2017-07-17 07:59:50,232: Perron eigenvalue is 0.00000; state equilibration timescale is ~ 1.0 iterations

Unsurprisingly, the dG estimate is very, very wrong in 0.16 (~ +90 kcal/mol), and relatively correct in 0.15 (~ -15 kcal/mol). Interestingly, yank analyze takesmuch longer in 0.16 (currently ~5 min vs. 20 seconds).

yank_mc.zip

[andrrizzi]

Hydration free energies in TIP4P-EW seem to be working with the latest openmmtools now!

[jchodera]

Thanks, @spadavec!

A quick manual inspection of system.xml suggests the cause: There are no virtual site definitions! The virtual sites have point masses set to zero, but instead of being updated by construction, they’re probably fixed in space because of the missing <VirtualSize> block. I’m surprised the binding free energies weren’t even crazier!

I think we neglected to properly handle virtual sites in AbsoluteAlchemicalFactory. This is one of the dangers of creating a new System from scratch instead of using a deep copy of System as a starting point and then removing Force objects (which is now possible)—a scheme I think we should switch our design to later on.

@andrrizzi : We’ll need to add virtual site support.