Fig. 2.

For each molecule in the SAMPL7 pK_a challenge we asked participants to predict the relative free energy between our selected neutral reference microstate and the rest of the enumerated microstates for that molecule. In this case, we asked for the relative state free energy including the proton free energy, which could also be called the reaction free energy for the microstate transition which has the reference state as the reactant and the alternate state as the product. Using SM43 as an example, participants were asked to predict the relative free energy between SM43_micro000 (our selected neutral microstate highlighted in yellow) and all of the other enumerated microstates (SM43_micro001–SM43_micro005) for a total of 5 relative state free energies ($\mathrm{\Delta }$G_BA, $\mathrm{\Delta }$G_CA, $\mathrm{\Delta }$G_DA, $\mathrm{\Delta }$G_EA, $\mathrm{\Delta }$G_FA). Some transitions involved a change in a single protonation state (e.g. the D–A transition of Figure 2) or tautomer (e.g. the C–A transition of Figure 2). A few cases involved a change of multiple protons (e.g. the F–A transition of Figure 2). All transitions were defined as away from the neutral reference state. Distinct microstates are defined as all tautomers of each charge state. For each relative free energy prediction reported, participants also submitted the formal charge after transitioning from the selected neutral state to the other state. For example, the reported charge state after transitioning from SM43_micro000 to SM43_micro001 would be − 1, SM43_micro000 to SM43_micro004 would be 0 (these are tautomers of each other), SM43_micro000 to SM43_micro005 would be + 1, and SM43_micro000 to SM43_micro003 would be + 2