Simulation Parameters. MD simulations in GROMACS were used to scan the conformational space within a solvated environment, as opposed to using ab initio molecular dynamics (AIMD) with a smaller number of solvent molecules as AIMD has a significantly higher computational cost (memory, disk space, CPU time) than conventional MD. The same parameters and force fields for creating the solvated environment for the physical MM submission were used for the Mixed submission. For all single point calculations following the simulation, non-equilibrium structures were used to prevent constrained optimizations to a local minimum from affecting the features that distinguish rotamers.